KR100812093B1 - Novel decursin derivative, the preparation thereof and a composition containing the same for treating and preventing cancer disease - Google Patents
Novel decursin derivative, the preparation thereof and a composition containing the same for treating and preventing cancer disease Download PDFInfo
- Publication number
- KR100812093B1 KR100812093B1 KR1020070012164A KR20070012164A KR100812093B1 KR 100812093 B1 KR100812093 B1 KR 100812093B1 KR 1020070012164 A KR1020070012164 A KR 1020070012164A KR 20070012164 A KR20070012164 A KR 20070012164A KR 100812093 B1 KR100812093 B1 KR 100812093B1
- Authority
- KR
- South Korea
- Prior art keywords
- oxo
- dimethyl
- ester
- chromen
- pyrano
- Prior art date
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- 238000002360 preparation method Methods 0.000 title abstract description 52
- 206010028980 Neoplasm Diseases 0.000 title abstract description 47
- 201000011510 cancer Diseases 0.000 title abstract description 43
- 239000000203 mixture Substances 0.000 title abstract description 43
- CUKSFECWKQBVED-INIZCTEOSA-N Decursin Chemical class C1=CC(=O)OC2=C1C=C1C[C@H](OC(=O)C=C(C)C)C(C)(C)OC1=C2 CUKSFECWKQBVED-INIZCTEOSA-N 0.000 title abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 15
- BGXFQDFSVDZUIW-LBPRGKRZSA-N decursinol Chemical compound O1C(=O)C=CC2=C1C=C1OC(C)(C)[C@@H](O)CC1=C2 BGXFQDFSVDZUIW-LBPRGKRZSA-N 0.000 claims abstract description 42
- BGXFQDFSVDZUIW-UHFFFAOYSA-N Decursinol Natural products O1C(=O)C=CC2=C1C=C1OC(C)(C)C(O)CC1=C2 BGXFQDFSVDZUIW-UHFFFAOYSA-N 0.000 claims abstract description 29
- 230000002265 prevention Effects 0.000 claims abstract description 14
- 240000001810 Angelica gigas Species 0.000 claims abstract description 9
- 235000018865 Angelica gigas Nutrition 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 230000036541 health Effects 0.000 claims abstract description 5
- 239000002243 precursor Substances 0.000 claims abstract description 5
- 235000013376 functional food Nutrition 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 39
- -1 3,4,5-triacetoxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H , 8H -pyrano [3,2-g] chromen-3-yl-ester compound Chemical class 0.000 claims description 23
- AFDXODALSZRGIH-UHFFFAOYSA-N p-coumaric acid methyl ether Natural products COC1=CC=C(C=CC(O)=O)C=C1 AFDXODALSZRGIH-UHFFFAOYSA-N 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 10
- 201000005202 lung cancer Diseases 0.000 claims description 10
- 208000020816 lung neoplasm Diseases 0.000 claims description 10
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 8
- 206010038038 rectal cancer Diseases 0.000 claims description 8
- 201000001275 rectum cancer Diseases 0.000 claims description 8
- 208000029742 colonic neoplasm Diseases 0.000 claims description 7
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- RYTCKGVIFSJEAD-UHFFFAOYSA-N (2,2-dimethyl-8-oxo-3,4-dihydropyrano[3,2-g]chromen-3-yl) 3-(2,5-dimethoxyphenyl)prop-2-enoate Chemical compound COC1=CC=C(OC)C(C=CC(=O)OC2C(OC3=CC=4OC(=O)C=CC=4C=C3C2)(C)C)=C1 RYTCKGVIFSJEAD-UHFFFAOYSA-N 0.000 claims description 6
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Classifications
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- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
- A61K36/232—Angelica
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
Landscapes
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- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
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Abstract
본 발명은 참당귀에서 분리된 (+)-데쿠르시놀(decursinol)을 전구체로 하여 합성한 데쿠르신 유도체(decursin derivative), 이의 제조방법 및 이를 포함하는 암 질환의 치료용 조성물에 관한 것이다. The present invention relates to a decursin derivative synthesized by using (+)-decursinol isolated from the Angelica gigas as a precursor, a preparation method thereof, and a composition for treating cancer diseases including the same.
본 발명의 데쿠르신 유도체(decursin derivative)는 암 세포에 대해 강한 세포독성을 나타냄으로써, 이를 포함하는 조성물은 암 질환의 예방 및 치료를 위한 약학 조성물 및 건강기능식품으로 유용하게 이용될 수 있다. The decursin derivative of the present invention exhibits strong cytotoxicity against cancer cells, so that the composition comprising the same may be usefully used as a pharmaceutical composition and health functional food for the prevention and treatment of cancer diseases.
데쿠르신 유도체, 참당귀, 데쿠르시놀, 항암 Decursin derivatives, Angelica, decursinol, anticancer
Description
본 발명은 참당귀에서 분리된 (+)-데쿠르시놀(decursinol)을 전구체로 하여 합성한 데쿠르신 유도체(decursin derivative)를 유효성분으로 함유하는 항암효과를 갖는 조성물에 관한 것이다. The present invention relates to a composition having an anticancer effect containing as an active ingredient a decursin derivative synthesized using (+)-decursinol isolated from a real Angelica as a precursor.
암은 여전히 심각한 임상적 문제이며, 인간의 건강관리 시스템에 있어 중대한 사회적 경제적 영향을 미치고 있다. Cancer is still a serious clinical problem and has a significant social and economic impact on human healthcare systems.
현대의학에 있어 진단, 예방, 치료의 발달에도 불구하고 여전히 세계적으로 수백만 명의 환자가 발생하고 있는 실정이다(Cheng YL et al., Anti-proliferative activity of Bupleurum scrozonerifolium in A549 human lung cancer cells in vitro and in vivo. Cancer Letters, 222(2), pp.183-93, 2005). 이러한 암의 유발 인자인 발암물질로는 흡연, 자외선, 화학물질, 음식물, 기타 환경인자들이 있으나, 그 유발 원인이 다양하여 치료제의 개발이 어려울 뿐만 아니라 발생하는 부위에 따 라 치료제의 효과 또한 각기 다르다. 현재 치료제로 사용되는 물질들은 상당한 독성을 지니고 있으며, 암 세포만을 선택적으로 제거하지 못하므로, 암의 발생 후 이의 치료뿐 아니라, 암의 발생을 예방하기 위한 독성이 적고 효과적인 항암제의 개발이 절실히 필요하다.Despite the development of diagnosis, prevention and treatment in modern medicine, there are still millions of patients worldwide (Cheng YL et al., Anti-proliferative activity of Bupleurum) scrozonerifolium in A549 human lung cancer cells in vitro and in vivo. Cancer Letters , 222 (2 ), pp. 183-93, 2005). The carcinogens that cause these cancers include smoking, ultraviolet rays, chemicals, foods, and other environmental factors. However, due to various causes, the development of therapeutic agents is difficult, and the effects of the therapeutic agents vary depending on the site of occurrence. . Currently, the substances used as therapeutic agents are extremely toxic and cannot selectively remove only cancer cells. Therefore, there is an urgent need for the development of low-toxic and effective anti-cancer agents to prevent cancer after treatment. .
세계적으로 매년 1,010만 명의 새로운 암 환자가 발생하고 600만 명이 암으로 사망하며, 이는 전체 사망의 12% 정도를 차지하고 있다. 이러한 추세가 계속되면 2020년경에는 매년 1,570만 명의 암 환자가 발생하고 1,000만 명이 암으로 사망할 것으로 추정된다. 우리나라 역시 1983년 이후로 한국인의 사망원인으로 암이 첫 번째 원인이 된 이후로 꾸준히 증가하고 있다. Every year, there are 10 million new cancer cases worldwide and 6 million people die of cancer, accounting for 12% of all deaths. If this trend continues, it is estimated that by 2020, 15.7 million cancer patients will die every year and 10 million will die from cancer. Korea has also been increasing steadily since cancer was the first cause of death in Korea since 1983.
화학 요법, 방사선 요법, 외과 요법, 유전자치료법 등 많은 방법들이 암 치료에 사용되지만 약물을 이용하는 화학 요법이 가장 많이 사용되고 있다. 그러나 화학 요법은 부작용이 크고 쉽게 완치되지 않아 암 치료를 위한 새로운 접근 방법이 필요하게 되었다. 크게 두 가지 접근 방법이 시도되고 있다. 첫째는 다양한 합성 방법을 통하여 기존의 항암제의 약효를 유지하는 한편 부작용은 현저히 줄어든 새로운 유도체를 합성, 개발하는 것이고 둘째는 암 발생 자체를 억제시키거나 암의 진행을 지연 혹은 역전시킴으로써 악성 암으로의 진행을 억제하는 화학적 암 예방(cancer chemoprevention)이다. Many methods, including chemotherapy, radiation therapy, surgical therapy, and gene therapy, are used to treat cancer, but chemotherapy using drugs is most commonly used. However, chemotherapy has many side effects and is not easily cured, requiring a new approach to cancer treatment. Two approaches are being attempted. The first is the synthesis and development of new derivatives that maintain the efficacy of the existing anticancer drugs through various synthetic methods and the side effects are significantly reduced. The second is the progression to malignant cancers by inhibiting cancer development itself or delaying or reversing the progression of cancer. It is chemical chemoprevention that inhibits cancer.
최근 선진 각국에서는 독성이 없고 효능이 뛰어난 화학적 암 예방제 및 항암제를 야채, 과일, 약용식물 등의 천연자원으로부터 개발하기 위해 많은 관심을 기울이고 있다(Kelloff et al., Annals New York Academy of Sciences, 889, pp.1- 13, 1999). In recent years, much attention has been paid in developing countries to develop nontoxic and efficacious chemical cancer preventives and anticancer agents from natural resources such as vegetables, fruits and medicinal plants (Kelloff et al., Annals) . New York Academy of Sciences , 889 , pp. 1-13, 1999).
화학적 암 예방은 외형상 건강한 사람을 대상으로 암 발생을 억제하기 위한 1차 예방, 양성암을 앓고 있는 사람을 대상으로 발암과정을 역전시키기 위한 2차 예방, 악성화, 전이, 합병증 등을 억제하고 암을 치료한 적이 있는 사람을 대상으로 재발을 예방하기 위한 3차 예방으로 단계적으로 적용할 수 있다. 따라서 암 예방 뿐만 아니라 치료제로서도 매우 유용하게 이용될 수 있다. Chemical cancer prevention is primarily intended to prevent cancer from appearing in healthy individuals and secondary prevention, malignancy, metastasis and complications to reverse the carcinogenic process in people with benign cancer. It can be applied step by step as a third prevention to prevent recurrence in people who have been treated. Therefore, it can be very useful as a therapeutic agent as well as cancer prevention.
데쿠르신은 당귀에서 추출되는 성분으로 1966년 일본에서 최초로 바디나물(Angelica decursiva Fr. et Sav.)에서 분리된 천연물질이며 데쿠르신이 한국산 참당귀(Angelica gigas Nakai)에 다량 함유되어 있다는 것은 1967년과 1969년(J., Pharm . Soc . Korea, 11, pp.22-26, 1967 ; 13, pp.47-50, 1969) 밝혀졌으며, 그 밖의 식물로는 기름나물(Peucedanum terevinthaceum Fisher et Turcz.)의 과실에서도 분리된 바 있다(한국약학회지, 30(2), pp.73-78, 1986).Decursin is an ingredient extracted from Angelica vulgaris. decursiv a Fr. et Sav.), a natural substance isolated from decursin and Angelica, Angelica gigas Nakai) was found in 1967 and 1969 (J., Pharm . Soc . Korea , 11 , pp.22-26, 1967; 13 , pp.47-50, 1969), and other plants The furnace has also been isolated from the fruit of the oil sprouts (Peucedanum terevinthaceum Fisher et Turcz.) (Korean Journal of Pharmacy, 30 (2) , pp.73-78, 1986).
데쿠르신은 암세포에 대해서는 강한 치사작용을 나타내는 반면, 정상세포에 대해서는 암세포에 대한 치사작용에 비해 훨씬 낮은 치사작용을 나타내어 항암제로서의 사용 가능성을 가지고 있다. 기존의 데쿠르신은 바디나물의 에테르 추출액으로부터 최초로 분리된 후, 한국산 당귀 및 기름나물의 과실에서도 분리되었다고 보고되었으나, 항암제로서 데쿠르신을 사용하려면 대량의 데쿠르신이 요구되며 데쿠르신의 활성을 증가시키기 위한 유도체의 개발은 중요한 의미를 갖는다. Decursin has a strong lethal action on cancer cells, while it has a far lower lethal action on cancer cells than on cancer cells, and has potential for use as an anticancer agent. Conventional decursins have been reported to have been separated from the fruit extracts of the body herb after the first separation, and also from the fruits of Korean Angelica and oil herb. The development of derivatives for these has important significance.
참당귀(Angelica gigas)는 미나리과(umbelliferae)의 식물로써 중국산을 중국당귀(Angelica sinesis), 일본산을 왜당귀(Angelica acutilobae), 한국산을 참당 귀(Angelica gigas)라고 한다. 예로부터 당귀는 어린순을 나물로 식용하고 뿌리를 진통효과, 신장독성 경감효과, 당뇨성 고혈압 치료 등 여러 가지 질환에 대한 약제로 사용하고 있다( Chi, H. J and Kim H. S. : Studies on the components of Umbelliferae Plants in Korea. Kor . J. Pharmacogn., 1, pp.25, 1970). 이러한 여러 가지 활성을 나타내는 주요한 성분은 dihydropyranocoumarin 계열의 물질인 (+)-데쿠르신(decursin), (+)-데쿠르시놀 안젤레이트(decursinol angelate)와 같이 (+)-데쿠르시놀(decursinol)[7-hydroxy-8,8-dimethyl-7,8-dihydro-6H-pyrano (3,2-g)chromen-2-one]의 secondary alcohol 기가 에스터화된 물질들이다(Bae, E. A. et al., Anti-Helicobacter pylori activity of herbal medicines. Biol Pharm Bull. 21, pp.990, 1998). Angelica Angelica gigas ) is a plant of the umbelliferae, and the Chinese Angelica ( Angelica) sinesis ), Japanese heron ( Angelica acutiloba e), Korean trellis ear ( Angelica gigas ). Since ancient times, Angelica has edible young shoots as herbs, and its roots have been used as a medicine for various diseases such as analgesic effect, renal toxicity alleviation, and treatment of diabetic hypertension (Chi, H. J and Kim HS: Studies on the components of Umbelliferae Plants in Korea. Kor. J. Pharmacogn., 1, pp.25, 1970). The main components exhibiting these various activities are (+)-decursinol, such as (+)-decursin and (+)-decursinol angelate, which are dihydropyranocoumarin-based substances. Secondary alcohol groups of 7-hydroxy-8,8-dimethyl-7,8-dihydro- 6H- pyrano (3,2-g) chromen-2-one] are esterified substances (Bae, EA et al., Anti -Helicobacter pylori activity of herbal medicines. Biol Pharm Bull . 21 , pp. 990, 1998).
최근에 참당귀에서 분리된 쿠마린 계열의 물질들이 앞서 설명한 여러 가지 약리학적 효과뿐만 아니라 항암효과를 나타낸다는 보고가 있어 주목을 끌고 있다(Kim, H. H. et al., Decursin and PDBu: Two PKC activators distinctively acting in the megakaryocytic differentiation of K562 human erythroleukemia cells. Leuk Res., 29, pp.1407, 2005). 따라서 (+)-데쿠르시놀(decursinol)을 출발물질로 하여 당귀에 존재하지 않는 다양한 구조의 에스터(ester) 형태의 새로운 유도체들을 합성하여 그들의 구조-활성간의 관계를 살펴보아 최적의 항암활성을 나타내는 물질을 도출하는 연구가 필요하리라 판단되어 본 발명을 완성하게 되었다. Recently, there have been reports that coumarin-based substances isolated from Angelica gigas have anti-cancer effects as well as the aforementioned pharmacological effects (Kim, HH et al., Decursin and PDBu: Two PKC activators distinctively acting) in the megakaryocytic differentiation of K562 human erythroleukemia cells. Leuk Res ., 29 , pp. 1407, 2005). Therefore, we synthesized new derivatives of ester forms of various structures that do not exist in Dong-guk using (+)-decursinol as starting material, and showed the optimal anticancer activity by examining the relationship between their structure-activity. It was concluded that a study for deriving a substance was needed to complete the present invention.
본 발명의 목적은 참당귀에서 분리된 (+)-데쿠르시놀(decursinol)을 전구체로 하여 합성한 신규 데쿠르신 유도체(decursin derivative) 및 이를 유효성분으로 함유하는 암 질환의 예방 및 치료를 위한 약학 조성물 및 건강기능식품을 제공하는 것이다.An object of the present invention is a novel decursin derivative synthesized by using (+)-decursinol isolated from a real Angelica as a precursor and a pharmaceutical for the prevention and treatment of cancer diseases containing the same as an active ingredient It is to provide a composition and dietary supplement.
상기 목적을 달성하기 위하여, 본 발명은 참당귀에서 분리된 (+)-데쿠르시놀(decursinol)을 전구체로 하여 합성된 하기 일반식 (I)로 표기되는 신규 구조의 데쿠르신 유도체(decursin derivative) 화합물 및 이의 약학적으로 허용가능한 염을 제공한다: In order to achieve the above object, the present invention is a decursin derivative of a novel structure represented by the following general formula (I) synthesized by using (+)-decursinol isolated from the real Angelica as a precursor Provided are compounds and pharmaceutically acceptable salts thereof:
(I) (I)
상기식에서, In the above formula,
R1은 하나이상의 R'로 치환되거나 비치환된 C1 내지 C20 알킬기, 알켄일기, 알키닐기 또는 A 치환기이며, 여기에서 R'는 할로겐원자, 니트로기, 아민기 또는 C1 내지 C4 저급 알킬기이며;R 1 is a C 1 to C 20 alkyl group, an alkenyl group, an alkynyl group or an A substituent which is unsubstituted or substituted with one or more R ′, wherein R ′ is a halogen atom, a nitro group, an amine group or a C 1 to C 4 lower group An alkyl group;
A 치환기는 A substituent
이며, 여기에서 A'는 o, m, p 위치에 하나 이상 치환 가능한 치환기이며, 수소원자, 히드록시기, 니트로기, 아세테이트기, 할로겐원자, C1 내지 C4 저급 알킬기, 저급 알콕시기 및 저급 알킬 에스테르 및 저급 알킬 카르복시기로부터 구성되는 군으로부터 선택된 하나 이상의 치환기이며;Where A 'is a substituent which may be substituted at least one at positions o, m and p , and is a hydrogen atom, a hydroxy group, a nitro group, an acetate group, a halogen atom, a C 1 to C 4 lower alkyl group, a lower alkoxy group and a lower alkyl ester And at least one substituent selected from the group consisting of lower alkyl carboxy groups;
n은 0 내지 4의 정수이다.n is an integer of 0-4.
상기 일반식 (I) 화합물의 바람직한 화합물군으로는 R1 은 할로겐원자 또는 C1 내지 C4 저급 알킬기로 치환되거나 비치환된 C1 내지 C10 알킬기, 알켄일기, 알키닐기 또는 A 치환기이며, 여기에서 A 치환기의 A'는 o, m, p 위치에 치환된 수소원자, 히드록시기, 메틸기, 에틸기, 메톡시기, 에톡시기, 니트로기 또는 아세틸기로부터 선택된 하나 이상의 치환기이며; n은 0 또는 1의 정수인 화합물군들이다.The formula (I) as a preferred compound group of compounds R 1 is substituted with a halogen atom or a C 1 to C 4 lower alkyl group, unsubstituted C 1 to C 10 alkyl group, an alkenyl group, an alkynyl group or an A substituent, and where A 'in the A substituent is at least one substituent selected from hydrogen atom, hydroxy group, methyl group, ethyl group, methoxy group, ethoxy group, nitro group or acetyl group substituted in o, m, p position; n is a group of compounds that is an integer of 0 or 1.
가장 바람직하게는 일반식 (I) 화합물로는 하기와 같은 화합물들을 들 수 있으며, 본 발명은 발명의 범위를 이에 제한하고자 함이 아니다. Most preferably, the compounds of the general formula (I) include the following compounds, and the present invention is not intended to limit the scope of the invention thereto.
3-메틸-부-2-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 시스-2-메틸-부-2-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 트란스-2-메틸-부-2-테노인산 2,2-디 메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 2-메틸-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 펜-2-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 부-3-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 펜-4-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 아세트산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 클로로-아세트산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 트리클로로-아세트산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 펜타노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 데카노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-페닐-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(3-히드록시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(3-아세톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(3,4-디히드록시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(3,4-디아세톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(4-히드록시-3-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(4-아세톡시-3-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라 노[3,2-g]크로멘-3-일-에스터, 3-(4-아세톡시-3,5-디메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(4-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(4-히드록시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(3,4-디메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(3,4,5-트리메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(3,4,5-트리히드록시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(2-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(2-히드록시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(3-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(2,3-디메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(2,4-디메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(2,5-디메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(2,4,5-트리메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3-(4-니트로-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 벤조인산 2,2-디메틸-8-옥소-3,4-디하이 드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터, 3,4,5-트리히드록시-벤조인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터 또는 3,4,5-트리아세톡시-벤조인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터.3-Methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl - ester, Cis -2-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl- Ester, trans -2-methyl-but-2-tenophosphate 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3 -Yl-ester, 2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, pen 2-Tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, but-3-te Senile acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, phen-4-tenophosphoric acid 2, 2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, acetic acid 2,2-dimethyl-8-oxo-3, 4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, chloro-acetic acid 2,2-dimethyl-8-oxo-3,4- Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, trichloroacetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H- Pyrano [3,2-g] chromen-3-yl-ester, pentanophosphate 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g ] Crommen-3-yl-ester, decanoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl- Ester, 3-phenyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3 -Hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- ( 3-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3,4-Dihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl- Ester, 3- (3,4-diacetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4 -Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4-hydroxy-3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8 -Oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4-acetoxy-3-methoxy-phenyl) -acrylic acid 2 , 2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4-acetoxy-3,5- Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4 -Methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- ( 4-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3,4-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester 3- (3,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -Pyrano [3,2-g] chromen-3-yl-ester, 3- (3,4,5-trihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4 -Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3, 4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3 , 4-Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo- 3,4-Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2,3-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8 -Oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2,4-dimethoxy-phenyl) -acrylic acid 2,2- Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2,5-dimethoxy-phenyl) -acrylic acid 2 , 2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (2,4,5-t Rimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3- (4 -Nitro-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, benzoic acid 2, 2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester, 3,4,5-trihydroxy-benzophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester or 3,4,5-triacetoxy-benzo Phosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester.
상기 일반식 (Ⅰ)로 표시되는 본 발명의 화합물들은 당해 기술분야에서 통상적인 방법에 따라 약학적으로 허용가능한 염으로 제조될 수 있다. The compounds of the present invention represented by the general formula (I) may be prepared as pharmaceutically acceptable salts according to methods conventional in the art.
염으로는 약학적으로 허용가능한 유리산 (free acid)에 의해 형성된 산부가염이 유용하다. 산 부가염은 통상의 방법, 예를 들면 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동몰량의 화합물 및 물 중의 산 또는 알코올 (예, 글리콜 모노메틸에테르)을 가열하고 이어서 상기 혼합물을 증발시켜서 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다. As salts are acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and acid or alcohol (eg, glycol monomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
이 때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 시트르산, 말레인산 (maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산 (propionic acid), 구연산 (citric acid), 젖산 (lactic acid), 글리콜산 (glycollic acid), 글루콘산 (gluconic acid), 갈락투론산, 글루탐산, 글루타르산 (glutaric acid), 글루쿠론산 (glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 히드로 아이오딕산 등을 사용할 수 있다.In this case, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리토 금속염은, 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리토 금속 수산화물 용액 중에 용해하고, 비용해 화합물염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이 때, 금속염으로서는 특히 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하며, 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리토 금속염을 적당한 은염 (예, 질산은)과 반응시켜 얻는다.Bases can also be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salts, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
상기의 일반식 (Ⅰ) 화합물의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 일반식 (Ⅰ) 화합물에 존재할 수 있는 산성 또는 염기성기의 염을 포함한다. 예를 들면, 약학적으로 허용가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨 염이 포함되며, 아미노기의 기타 약학적으로 허용가능한 염으로는 히드로브로마이드, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄설포네이트 (메실레이트) 및 p-톨루엔설포네이트 (토실레이트) 염이 있으며, 당업계에서 알려진 염의 제조방법이나 제조과정을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the above compounds of formula (I) include salts of acidic or basic groups which may be present in compounds of formula (I), unless otherwise indicated. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, which are known in the art. It can be prepared through.
본 발명의 다른 목적은 상기 일반식 (Ⅰ) 화합물의 제조방법을 제공하는 것으로, 하기의 반응식들에 도시된 방법에 의해 화학적으로 합성될 수 있지만, 이들 예로만 한정되는 것은 아니다. Another object of the present invention is to provide a method for preparing the compound of Formula (I), which may be chemically synthesized by the method shown in the following schemes, but is not limited thereto.
하기의 반응식들은 본 발명의 대표적인 화합물들의 제조방법을 제조 단계별로 나타내는 것으로 본 발명의 여러 화합물들은 반응식 1 내지 반응식 3의 합성과정에서 사용되는 시약, 용매 및 반응 순서를 바꾸는 등의 작은 변경으로 제조될 수 있다. 본 발명의 몇몇 화합물들은 반응식 1 내지 반응식 3의 범주에 포함되지 않는 과정에 따라 합성되었으며, 이러한 화합물들에 대한 상세한 합성 과정은 이들 각각의 실시예에 설명되어 있다.The following reaction schemes represent the preparation steps of the representative compounds of the present invention. The various compounds of the present invention may be prepared by small changes such as changing the reagents, solvents, and reaction sequences used in the synthesis of Schemes 1 to 3. Can be. Some compounds of the present invention have been synthesized according to processes not included in the scope of Schemes 1 through 3, and detailed synthesis procedures for these compounds are described in their respective examples.
반응식 (1)은 (+)-데쿠르시놀(decursinol)에 다양한 치환기를 갖는 카르복실산(1-9a) 또는 알카노일클로라이드(10-12a)를 반응시켜 다양한 알킬기(alkyl group) 치환체를 갖는 데쿠르신 유도체(decursin derivative)(1-12b)를 제조하는 과정을 나타낸다. Scheme (1) is a deco having various alkyl group substituents by reacting (+)-decursinol with carboxylic acid (1-9a) or alkanoyl chloride (10-12a) having various substituents. A process for preparing a decursin derivative (1-12b) is shown.
반응식 (a)의 제 1단계에서는 (+)-데쿠르시놀(decursinol), 카르복실산(carboxylic acid), 디사이클로헥실카보디이미드(DCC) 및 디메틸아미노피리딘(DMAP)을 무수 디클로로메탄으로 용해시킨다. 또한 반응식 (b)의 제 1단계에서는 (+)-데쿠르시놀(decursinol), 알카노일클로라이드(acyl chloride) 및 피리딘(pyridine)을 무수 디클로로메틴으로 용해시킨다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 디클로로메탄, 클로로포름, 디에틸에테르, 테트라하이드로푸란 등을 이용하여 반응을 수행한다. 반응 온도는 특별히 제한되지는 않으나, 일반적으로 냉온 내지 상온에서 수행할 수 있고, 바람직하게는 상온에서 수행한다. 반응 시간은 5시간 내지 24시간동안 수행할 수 있고, 바람직하게는 24시간동안 교반시켜 다양한 알킬 치환체를 갖는 데쿠르신 유도체(1b-12b)를 합성할 수 있다. In the first step of Scheme (a), (+)-decursinol, carboxylic acid, dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) are dissolved with anhydrous dichloromethane. Let's do it. In addition, in the first step of Scheme (b), (+)-decursinol, alkanoyl chloride and pyridine are dissolved with anhydrous dichloromethine. The solvent used at this time is carried out using a solvent that does not adversely affect the reaction, dichloromethane, chloroform, diethyl ether, tetrahydrofuran and the like. The reaction temperature is not particularly limited, but may be generally performed at cold to room temperature, and preferably at room temperature. The reaction time can be carried out for 5 to 24 hours, preferably stirred for 24 hours to synthesize decursin derivatives (1b-12b) having various alkyl substituents.
반응식 (2)는 (+)-데쿠르시놀(decursinol)에 다양한 치환기를 갖는 신남산(cinnamic acid)을 반응시켜 다양한 시나모일(cinnamoyl group) 치환체를 갖는 데쿠르신 유도체(decursin derivative)를 제조하는 과정을 나타낸다. Scheme (2) is a process for preparing a decursin derivative having various cinnamoyl group substituents by reacting cinnamic acid with various substituents to (+)-decursinol. Indicates.
제 1단계에서는 아세트산 무수물, 3-또는 4-(OH)n -신남산(cinnamic acid) 및 피리딘(pyridine)을 첨가한다. 반응 온도는 특별히 제한되지는 않으나, 일반적 으로 냉온 내지 상온에서 수행할 수 있고, 바람직하게는 상온에서 수행한다. 제 2단계에서는 신남산(cinnamic acid)을 무수 벤젠으로 용해시켜, 여기에 N,N-디메틸포름아마이드와 티오닐클로라이드를 넣어 화합물을 합성하여 산 할라이드체를 얻고, 제 3단계에서는 (+)-데쿠르시놀(decursinol)과 피리딘(pyridine)을 무수 디클로로메탄으로 용해시키고 시나모일 클로라이드를 첨가하여 시나모일 치환체를 갖는 유도체 화합물을 제조한다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 디클로로메탄, 클로로포름 등을 이용하여 반응을 수행한다. 반응 온도는 특별히 제한되지는 않으나, 일반적으로 냉온 내지 상온에서 수행하고, 바람직하게는 상온에서 수행한다. 제 4단계에서는 3-또는 4-(OAC)n -시나모일 치환체를 갖는 유도체를 아세톤에 용해시킨 후, 3N염산(3N HCl)을 적가하여 환류시킨 후 실온에서 냉각하여 감압농축 시켜 반응을 수행한다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매의 존재 하에서 수행하며, 이러한 목적으로 사용될 수 있는 용매의 예로는 디메틸포름아미드, 메탄올, 에탄올 등의 알콜 용매 또는 아세톤을 사용하여 반응을 수행할 수 있고, 바람직하게는 아세톤을 사용하여 수행한다. 제 5단계에서는 3-, 4 또는 5-(OCH3)n -시나모일 치환체를 갖는 유도체를 디클로로메탄에 용해시킨 후, 1M 보론 트리브로마이드 용액(1M BBr3 in MC)을 적가시켜 반응을 수행한다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 디클로로메탄, 클로로포름 등을 이용하여 반응을 수행한다. 반응 온도는 일반적으로 냉온 내지 상온에서 수행하고, 바람직하게는 냉온에서 수행한다. In the first step acetic anhydride, 3- or 4- (OH) n -cinnamic acid and pyridine are added. The reaction temperature is not particularly limited, but can be generally performed at cold to room temperature, preferably at room temperature. In the second step, cinnamic acid is dissolved in anhydrous benzene, and N, N -dimethylformamide and thionyl chloride are added thereto to synthesize a compound to obtain an acid halide. In the third step, (+)- Decursinol and pyridine are dissolved in anhydrous dichloromethane and cinnamoyl chloride is added to prepare derivative compounds with cinnamoyl substituents. At this time, the solvent is used to perform the reaction using a solvent that does not adversely affect the reaction, dichloromethane, chloroform and the like. The reaction temperature is not particularly limited, but is generally carried out at cold to room temperature, preferably at room temperature. In the fourth step, a derivative having a 3- or 4- (OA C ) n -cinamoyl substituent is dissolved in acetone, 3N hydrochloric acid (3N HCl) is added dropwise to reflux, and cooled at room temperature to be concentrated under reduced pressure to carry out the reaction. do. At this time, the solvent used is carried out in the presence of a solvent that does not adversely affect the reaction, examples of the solvent that can be used for this purpose may be carried out using an alcohol solvent such as dimethylformamide, methanol, ethanol or acetone , Preferably using acetone. In the fifth step, a derivative having a 3-, 4 or 5- (OCH 3 ) n -cinamoyl substituent is dissolved in dichloromethane, and then a reaction is performed by dropwise adding a 1M boron tribromide solution (1M BBr 3 in MC). . At this time, the solvent is used to perform the reaction using a solvent that does not adversely affect the reaction, dichloromethane, chloroform and the like. The reaction temperature is generally carried out at cold to room temperature, preferably at cold temperature.
반응식 (3)은 데쿠르시놀(decursinol)에 다양한 치환기를 갖는 벤조인산(benzoic acid)을 반응시켜 다양한 벤조일(benzoyl group) 치환체를 갖는 데쿠르신 유도체(decursin derivative)를 제조하는 과정을 나타낸다. Scheme (3) represents a process of preparing decursin derivatives having various benzoyl group substituents by reacting decursinol with benzoic acid having various substituents.
제 1단계에서는 아세트산 무수물과 3,4,5-(OH)3-벤조인산을 용해시킨 후, 농축황산을 적가하고 환류시켜 반응을 수행하여 화합물을 얻는다. 제 2단계에서는 벤조인산을 무수 벤젠으로 용해시킨 후, N,N-디메틸포름아미드와 티오닐클로라이드를 넣어 환류시켰다. 제 3단계에서는 (+)-데쿠르시놀과 피리딘을 무수 디클로로메탄으로 용해시키고 벤조일 클로라이드를 첨가하여 산 할라이드체 화합물을 제조한다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 디클로로메탄, 클로로포름 등을 이용하여 반응을 수행한다. 반응 온도는 특별히 제한되지는 않으나, 일반적으로 냉온 내지 상온에서 수행하고, 바람직하게는 상온에서 수행한다. 제 4단계에서는 3,4,5-(OAC)3-벤조일 데쿠르신 유도체를 아세톤에 용해시킨 후, 3N 염산(3NHCl)을 적가하여 환류시켜 벤조일 치환체를 갖는 화합물을 제조한다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 디메틸포름아미드, 메탄올, 에 탄올 등의 알콜 용매 또는 아세톤을 사용하여 반응을 수행한다. In the first step, acetic anhydride and 3,4,5- (OH) 3 -benzoic acid are dissolved, and concentrated sulfuric acid is added dropwise and refluxed to obtain a compound. In the second step, benzoic acid was dissolved in anhydrous benzene, and N, N -dimethylformamide and thionyl chloride were added to reflux. In the third step, an acid halide compound is prepared by dissolving (+)-decurinol and pyridine with anhydrous dichloromethane and adding benzoyl chloride. At this time, the solvent is used to perform the reaction using a solvent that does not adversely affect the reaction, dichloromethane, chloroform and the like. The reaction temperature is not particularly limited, but is generally carried out at cold to room temperature, preferably at room temperature. In the fourth step, a 3,4,5- (OA C ) 3 -benzoyl decursin derivative is dissolved in acetone, and then refluxed with 3N hydrochloric acid (3NHCl) dropwise to prepare a compound having a benzoyl substituent. In this case, the solvent used is an alcohol solvent such as dimethylformamide, methanol, ethanol, or acetone, which do not adversely affect the reaction.
상기 제조방법으로 얻어진 일반식 (I) 화합물들은 폐암세포인 A549, 대장암세포인 HCT15 및 직장암세포인 ACHN와 같은 암세포에 대한 세포독성효과를 확인하여 본 발명의 데쿠르신 유도체(decursin derivative) 화합물들은 암 질환의 예방 및 치료를 위한 약학 조성물 및 건강기능식품으로 유용하게 사용될 수 있다. The general formula (I) compounds obtained by the above production method confirmed the cytotoxic effects on cancer cells such as lung cancer cells A549, colon cancer cells HCT15, and rectal cancer cells ACHN, and the decursin derivative compounds of the present invention are cancers. It can be usefully used as a pharmaceutical composition and health functional food for the prevention and treatment of diseases.
따라서, 본 발명은 상기 일반식 (I)으로 표기되는 데쿠르신 유도체(decursin derivative)화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암 질환의 예방 및 치료를 위한 약학조성물을 제공한다. Accordingly, the present invention provides a pharmaceutical composition for the prevention and treatment of cancer diseases containing a decursin derivative compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 암 질환은 일반적인 암 질환들을 포함하며, 바람직하게는 위암, 결장암, 유방암, 폐암, 비소세포성폐암, 골암, 췌장암, 피부암, 두부 또는 경부암, 피부 또는 안구 내 흑색종, 자궁암, 난소암, 대장암, 소장암, 직장암, 항문부근암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 소장암, 임파선암, 방광암, 담낭암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신장세포 암종, 신장골반 암종, 중추신경계(CNS; central nervous system) 종양, 1차 CNS 림프종, 척수 종양, 뇌간 신경교종 또는 뇌하수체 선종, 보다 바람직하게는 폐암, 대장암, 직장암을 포함한다. The cancer disease includes general cancer diseases, preferably gastric cancer, colon cancer, breast cancer, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma in the skin or eye, uterine cancer, ovarian cancer, large intestine Cancer, small bowel cancer, rectal cancer, anal muscle cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, lymph gland cancer, bladder cancer, gallbladder cancer, endocrine cancer , Thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocyte lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS; central) nervous system) tumors, primary CNS lymphoma, spinal cord tumors, brainstem glioma or pituitary adenoma, more preferably lung cancer, colon cancer, rectal cancer.
본 발명의 화합물을 포함하는 조성물은 통상의 방법에 따른 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다. Compositions comprising a compound of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.
본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 본 발명의 화합물을 포함하는 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The compositions comprising the compounds of the present invention are each formulated in the form of oral dosage forms, external preparations, suppositories, or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., in accordance with conventional methods. Can be used.
상세하게는, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스 (sucrose), 락토오스 (lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.Specifically, when formulated, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose in the extract. ), Lactose, gelatin and the like can be mixed. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used. Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명의 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 화합물은 0.0001 ~ 100 mg/kg으로, 바람직하게는 0.001 ~ 100 mg/kg의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다. 조성물에서 본 발명의 화합물은 전체 조성물 총 중량에 대하여 0.0001 ~ 50 중량%의 함량으로 배합될 수 있다. Preferred dosages of the compounds of the present invention depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably in an amount of 0.001 to 100 mg / kg once to several times daily. The compound of the present invention in the composition may be formulated in an amount of 0.0001 to 50% by weight based on the total weight of the total composition.
또한, 본 발명의 화합물의 약학적 투여 형태는 이들의 약학적 허용가능한 염의 형태로도 사용될 수 있고, 또한 단독으로 또는 타 약학적 활성 화합물과 결합뿐만 아니라 적당한 집합으로 사용될 수 있다. In addition, the pharmaceutical dosage forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.
본 발명의 약학 조성물은 쥐, 마우스, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 (intracerebroventricular) 주사에 의해 투여될 수 있다. The pharmaceutical composition of the present invention can be administered to mammals such as mice, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
본 발명은 암 질환의 예방 및 치료 효과를 나타내는 일반식 (I)의 데쿠르신 유도체(decursin derivative) 화합물을 유효성분으로 함유하는 암 질환의 예방 및 개선용 건강기능식품을 제공한다.The present invention provides a dietary supplement for the prevention and improvement of cancer diseases, comprising as an active ingredient a decursin derivative compound of the general formula (I), which shows the effect of preventing and treating cancer diseases.
본 발명의 화합물은 암 질환의 예방 및 개선을 위한 약제, 식품 및 음료 등 에 다양하게 이용될 수 있다. 본 발명의 화합물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.Compounds of the present invention can be used in a variety of drugs, food and beverages for the prevention and improvement of cancer diseases. Examples of the food to which the compound of the present invention may be added include various foods, beverages, gums, teas, vitamin complexes, health supplements, and the like, and may be used in the form of powders, granules, tablets, capsules, or beverages. have.
본 발명의 화합물은 독성 및 부작용은 거의 없으므로 예방 목적으로 장기간 복용 시에도 안심하고 사용할 수 있는 약제이다. Since the compound of the present invention has little toxicity and side effects, it is a drug that can be used safely even for long-term administration for the purpose of prevention.
본 발명의 상기 화합물은 암 질환의 예방 및 치료를 목적으로 식품 또는 음료에 첨가될 수 있다. 이 때, 식품 또는 음료 중의 상기 화합물의 양은 일반적으로 본 발명의 건강식품 조성물은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 ㎖를 기준으로 0.02 내지 30 g, 바람직하게는 0.3 내지 10 g의 비율로 가할 수 있다. The compounds of the present invention can be added to food or beverages for the purpose of preventing and treating cancer diseases. At this time, the amount of the compound in the food or beverage is generally added to the health food composition of the present invention to 0.01 to 15% by weight of the total food weight, the health beverage composition is 0.02 to 30 g based on 100 ml, preferably Can be added in a ratio of 0.3 to 10 g.
본 발명의 건강 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 것 외에 액체성분에는 특별한 제한점은 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등의 디사카라이드, 예를 들어 말토스, 슈크로스 등의 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g이다. The health beverage composition of the present invention, in addition to containing the compound as an essential ingredient in the indicated proportions, has no particular limitation on the liquid component and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. Examples of the above-mentioned natural carbohydrates are conventional monosaccharides such as disaccharides such as glucose and fructose, such as maltose, sucrose and the like, and polysaccharides such as dextrin, cyclodextrin and the like. Sugars and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally about 1-20 g, preferably about 5-12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 화합물은 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 조성물들은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다. In addition to the compounds of the present invention, the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid And salts thereof, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. The compositions of the present invention may also contain pulp for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but is generally selected from the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명한다. Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 한정되는 것은 아니다. However, the following Examples and Experimental Examples are only illustrative of the present invention, and the content of the present invention is not limited to the following Examples and Experimental Examples.
실시예Example 1. 3- 1-3 메틸methyl -부-2-Part-2- 테노인산Tennophosphate 2,2-디메틸-8-옥소-3,4- 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -피라노[-Pyrano [ 3,2-g]크로멘3,2-g] chromen -3-일-에스터(1b)의 제조Preparation of 3-yl-ester (1b)
상기 반응식에서 나타난 바와 같이 (+)-데쿠르시놀(decursinol)과 라운드 플라스크에 1당량의 3-메틸-부-2-테노인산, 1.1-2.0당량의 1,3-디사이클로헥실카보디이미드(DCC) 및 0.4 당량의 4-디메틸아미노피리딘(DMAP)을 넣고 무수 디클로로메탄으로 용해하였다. 반응혼액에 1당량의 데쿠르시놀을 넣고 실온에서 24시간 교반하였다. 반응혼액은 디클로로메탄으로 세척하며 여과하였고, 여액은 감압농축하였다. 순수한 생성물(1b)을 얻기 위해 농축액은 이동상(n-헥산 : 에틸아세테이드 = 10:1 ~ 1:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하여 하기 물성치를 갖는 3-메틸-부-2-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(1b)를 얻었다. As shown in the reaction scheme, 1 equivalent of 3-methyl-but-2-tenophosphoric acid, 1.1-2.0 equivalents of 1,3-dicyclohexylcarbodiimide in a round flask with (+)-decursinol (DCC) and 0.4 equivalent of 4-dimethylaminopyridine (DMAP) were added and dissolved in anhydrous dichloromethane. 1 equivalent of decursinol was added to the reaction mixture, which was stirred for 24 hours at room temperature. The reaction mixture was washed with dichloromethane and filtered, and the filtrate was concentrated under reduced pressure. To obtain the pure product (1b), the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1) to give 3-methyl-but- 2-Tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (1b) was obtained.
수율 : 64.0%;Yield: 64.0%;
반고체상(Semi solid);Semi solid;
Rf=0.35(n-헥산:에틸아세테이트=2:1);R f = 0.35 (n-hexane: ethyl acetate = 2: 1);
1H NMR(CDCl3, 400MHz) : δ ppm 7.589(d, J=9.6Hz, 1H), 7.160(s, 1H), 6.788(s, 1H), 6.222(d, J=9.6Hz, 1H), 5.663(s, 1H), 5.086(t, J=4.8Hz, 1H), 3.197(dd, J=4.8, 17.2Hz, 1H), 2.867(dd, J=4.8, 17.2Hz, 1H), 2.146(d, J=1.0Hz, 3H), 1.880(d, J=1.0Hz, 3H), 1.384(s, 3H), 1.365(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.589 (d, J = 9.6 Hz, 1 H), 7.160 (s, 1 H), 6.788 (s, 1 H), 6.222 (d, J = 9.6 Hz, 1 H), 5.663 (s, 1H), 5.086 (t, J = 4.8 Hz, 1H), 3.197 (dd, J = 4.8, 17.2 Hz, 1H), 2.867 (dd, J = 4.8, 17.2 Hz, 1H), 2.146 (d , J = 1.0 Hz, 3H), 1.880 (d, J = 1.0 Hz, 3H), 1.384 (s, 3H), 1.365 (s, 3H);
MS(m/z) 329 (M+H)+.MS ( m / z ) 329 (M + H) + .
실시예 2. Example 2. 시스Sheath -2-메틸-부-2-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2-Methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(2b)의 제조Preparation of Pyrano [3,2-g] chromen-3-yl-ester (2b)
(+)-데쿠르시놀(decursinol)과 라운드 플라스크에 1당량의 3-메틸-부-2-테노인산 대신 시스-2-메틸-부-2-테노인산으로 바꾸는 점만 제외하고 상기 실시예 1의 반응과 동일한 반응 공정을 수행하여 하기 물성치를 갖는 시스-2-메틸-부-2-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(2b)를 얻었다.The above example except that in a round flask with (+)-decursinol was replaced with cis -2-methyl-but - 2-tenophosphoric acid instead of one equivalent of 3-methyl-but-2-tenophosphoric acid. The same reaction process as in 1 was carried out to carry cis -2-methyl-but-2-tenophosphate 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano having the following physical properties. [3,2-g] chromen-3-yl-ester (2b) was obtained.
수율 : 56.3%;Yield: 56.3%;
오일상(oil);Oil phase;
Rf=0.35(n-헥산:에틸아세테이트=2:1);R f = 0.35 (n-hexane: ethyl acetate = 2: 1);
1H NMR(CDCl3, 400MHz): δ ppm 7.595(d, J=9.2Hz, 1H), 7.167(s, 1H), 6.819(qd, J=6.8, 1.2Hz, 1H), 6.790(s, H), 6.223(d, J=9.2Hz, 1H), 5.092(t, J=5.4Hz, 1H), 3.214(dd, J=4.8, 17.2Hz, 1H), 2.888(dd, J=5.4, 17.2Hz, 1H), 1.803(d, J=1.2Hz, 3H), 1.767(d, J=6.8Hz, 3H), 1.398(s, 3H), 1.378(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.595 (d, J = 9.2 Hz, 1H), 7.167 (s, 1H), 6.819 (qd, J = 6.8, 1.2 Hz, 1H), 6.790 (s, H ), 6.223 (d, J = 9.2Hz, 1H), 5.092 (t, J = 5.4Hz, 1H), 3.214 (dd, J = 4.8, 17.2Hz, 1H), 2.888 (dd, J = 5.4, 17.2Hz , 1H), 1.803 (d, J = 1.2 Hz, 3H), 1.767 (d, J = 6.8 Hz, 3H), 1.398 (s, 3H), 1.378 (s, 3H);
MS(m/z) 329 (M+H)+.MS ( m / z ) 329 (M + H) + .
실시예Example 3. 3. 트란스Trans -2--2- 메틸methyl -부-2-Part-2- 테노인산Tennophosphate 2,2-디메틸-8-옥소-3,4- 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(3b)의 제조Preparation of 3-yl-ester (3b)
(+)-데쿠르시놀(decursinol)과 라운드 플라스크에 1당량의 3-메틸-부-2-테노인산 대신 트란스-2-메틸-부-2-테노인산으로 바꾸는 점만 제외하고 상기 실시예 1의 반응과 동일한 반응 공정을 수행하여 하기 물성치를 갖는 트란스-2-메틸-부-2-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(3b)를 얻었다.The above example except that transcuring with (+)-decursinol and trans -2-methyl-but-2-tenophosphoric acid instead of one equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask The same reaction process as in the reaction of 1 was carried out to give trans -2-methyl-but-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano having the following physical properties. [3,2-g] chromen-3-yl-ester (3b) was obtained.
수율 : 43.9%;Yield: 43.9%;
오일상(Oil);Oil phase;
Rf=0.48 (n-헥산:에틸아세테이트=2:1);R f = 0.48 (n-hexane: ethyl acetate = 2: 1);
1H NMR(CDCl3, 400MHz): δppm 7.505(d, J=9.6Hz, 1H), 7.074(s, 1H), 6.743(m, 2H), 6.154(d, J=9.6Hz, 1H), 5.009(t, J=4.8Hz, 1H), 3.133(dd, J=4.8, 17.2Hz, 1H), 2.806(dd, J=4.8, 17.2Hz, 1H), 1.784(m, 6H), 1.352(s, 3H), 1.319(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.505 (d, J = 9.6 Hz, 1H), 7.074 (s, 1H), 6.743 (m, 2H), 6.154 (d, J = 9.6 Hz, 1H), 5.009 (t, J = 4.8 Hz, 1H), 3.133 (dd, J = 4.8, 17.2 Hz, 1H), 2.806 (dd, J = 4.8, 17.2 Hz, 1H), 1.784 (m, 6H), 1.352 (s, 3H), 1.319 (s, 3H);
MS(m/z) 329 (M+H)+.MS ( m / z ) 329 (M + H) + .
실시예 4. 2-메틸-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 4. 2-Methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2- g]크로멘-3-일-에스터(4b)의 제조Preparation of pyrano [3,2-g] chromen-3-yl-ester (4b)
(+)-데쿠르시놀(decursinol)과 라운드 플라스크에 1당량의 3-메틸-부-2-테노인산 대신 2-메틸-아크릴산으로 바꾸는 점만 제외하고 상기 실시예 1의 반응과 동일한 반응 공정을 수행하여 하기 물성치를 갖는 2-메틸-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(4b)를 얻었다.The same reaction process as in Example 1 was carried out except that (+)-decursinol was changed to 2-methyl-acrylic acid instead of 1 equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask. 2-methyl-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester having the following physical properties 4b).
수율 : 93.3%;Yield: 93.3%;
반고체상(Semi Solid);Semi Solid;
Rf=0.52(n-헥산:에틸아세테이트=1:1) ;R f = 0.52 (n-hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3, 400MHz): δppm 7.565(d, J=9.6Hz, 1H), 7.141(s, 1H), 6.786(s, 1H), 6.216(d, J=9.6Hz, 1H), 6.052(s, 1H), 5.562(s, 1H), 5.076(t, J=5.2Hz, 1H), 3.209(dd, J=4.8, 16.8Hz, 1H), 2.883(dd, J=5.6, 17.2Hz, 1H), 1.903(s, 3H), 1.384(s, 3H), 1.370(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.565 (d, J = 9.6 Hz, 1H), 7.141 (s, 1H), 6.786 (s, 1H), 6.216 (d, J = 9.6 Hz, 1H), 6.052 (s, 1H), 5.562 (s, 1H), 5.076 (t, J = 5.2 Hz, 1H), 3.209 (dd, J = 4.8, 16.8 Hz, 1H), 2.883 (dd, J = 5.6, 17.2 Hz, 1H), 1.903 (s, 3H), 1.384 (s, 3H), 1.370 (s, 3H);
MS(m/z) 315 (M+H)+.MS ( m / z ) 315 (M + H) + .
실시예 5. 펜-2-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 5. Phen-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(5b)의 제조Preparation of Pyrano [3,2-g] chromen-3-yl-ester (5b)
(+)-데쿠르시놀(decursinol)과 라운드 플라스크에 1당량의 3-메틸-부-2-테노인산 대신 펜-2-테노인산으로 바꾸는 점만 제외하고 상기 실시예 1의 반응과 동 일한 반응 공정을 수행하여 하기 물성치를 갖는 펜-2-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(5b)를 얻었다.Same as the reaction of Example 1, except that (+)-decursinol was replaced with phen-2-tenophosphoric acid instead of 1 equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask. Phen-2-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3 having the following physical properties -Yl-ester (5b) was obtained.
수율 : 92.1%;Yield: 92.1%;
오일상(Oil);Oil phase;
Rf=0.400(n-헥산:에틸아세테이트=2:1);R f = 0.400 (n-hexane: ethyl acetate = 2: 1);
1H NMR(CDCl3, 400MHz): δppm 7.58(d, J=9.6Hz, 1H), 7.151(s, 1H), 7.028(m, 1H), 6.798(s, 1H), 6.223(d, J=9.6Hz, 1H), 5.803(d, J=15.6Hz, 1H), 5.111(t, J=4.8Hz, 1H), 3.204(dd, J=4.8, 17.2Hz, 1H), 2.882 (dd, J=4.8, 17.2Hz, 1H), 2.197(m, 2H), 1.390(s, 3H), 1.366(s, 3H), 1.049(t, J=7.6Hz, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.58 (d, J = 9.6 Hz, 1H), 7.151 (s, 1H), 7.028 (m, 1H), 6.798 (s, 1H), 6.223 (d, J = 9.6 Hz, 1H), 5.803 (d, J = 15.6 Hz, 1H), 5.111 (t, J = 4.8 Hz, 1H), 3.204 (dd, J = 4.8, 17.2 Hz, 1H), 2.882 (dd, J = 4.8, 17.2 Hz, 1H), 2.197 (m, 2H), 1.390 (s, 3H), 1.366 (s, 3H), 1.049 (t, J = 7.6 Hz, 3H);
MS(m/z) 329 (M+H)+.MS ( m / z ) 329 (M + H) + .
실시예 6. 부-3-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 6. But-3-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(6b)의 제조Preparation of Pyrano [3,2-g] chromen-3-yl-ester (6b)
(+)-데쿠르시놀(decursinol)과 라운드 플라스크에 1당량의 3-메틸-부-2-테노인산 대신 부-3-테노인산으로 바꾸는 점만 제외하고 상기 실시예 1의 반응과 동일한 반응 공정을 수행하여 하기 물성치를 갖는 부-3-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(6b)를 얻었다.Same reaction as in Example 1, except that (+)-decursinol was replaced with but-3-tenophosphoric acid instead of 1 equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask Butanetenenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3- One-ester (6b) was obtained.
수율 : 90.2%;Yield: 90.2%;
반고체상(Semi Solid);Semi Solid;
Rf=0.65(n-헥산:에틸아세테이트=1:1);R f = 0.65 (n-hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3, 400MHz): δppm 7.584(d, J=9.6Hz, 1H), 7.154(s, 1H), 6.793(s, 1H), 6.232(d, J=9.6Hz, 1H), 5.866(m, 1H), 5.176(m, 2H), 5.063(t, J=4.8Hz, 1H), 3.190(dd, J=4.8, 17.2Hz, 1H), 3.096(m, 2H), 2.856(dd, J=5.2, 17.2Hz, 1H), 1.373(s, 3H), 1.355(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.584 (d, J = 9.6 Hz, 1H), 7.154 (s, 1H), 6.793 (s, 1H), 6.232 (d, J = 9.6 Hz, 1H), 5.866 (m, 1H), 5.176 (m, 2H), 5.063 (t, J = 4.8 Hz, 1H), 3.190 (dd, J = 4.8, 17.2 Hz, 1H), 3.096 (m, 2H), 2.856 (dd, J = 5.2, 17.2 Hz, 1 H), 1.373 (s, 3 H), 1.355 (s, 3 H);
MS(m/z) 315 (M+H)+.MS ( m / z ) 315 (M + H) + .
실시예 7. 펜-4-테노인산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 7. Phen-4-tenophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(7b)의 제조Preparation of pyrano [3,2-g] chromen-3-yl-ester (7b)
(+)-데쿠르시놀(decursinol)과 라운드 플라스크에 1당량의 3-메틸-부-2-테노인산 대신 펜-4-테노인산으로 바꾸는 점만 제외하고 상기 실시예 1의 반응과 동일한 반응 공정을 수행하여 하기 물성치를 갖는 펜-4-테노익 액시드 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(7b)를 얻었다.The same reaction as in Example 1, except that (+)-decursinol was changed to phen-4-tenophosphoric acid instead of 1 equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask. Phen-4-tenoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3 having the following physical properties by carrying out the process -Work-ester (7b) was obtained.
수율 : 81.0%;Yield: 81.0%;
오일상(Oil);Oil phase;
Rf=0.51(n-헥산:에틸아세테이트=2:1);R f = 0.51 (n-hexane: ethyl acetate = 2: 1);
1H NMR(CDCl3, 400MHz): δppm 7.580(d, J=9.6Hz, 1H), 7.146(s, 1H), 6.792(s, 1H), 6.231(d, J=9.6Hz, 1H), 5.790(m, 1H), 5.056-4.957(m, 3H), 3.178(dd, J=4.8, 17.2Hz, 1H), 2.837 (dd, J=5.2, 17.2Hz, 1H), 2.433(m, 2H), 2.356(t, J=6.4Hz, 2H), 1.374(s, 3H), 1.352(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.580 (d, J = 9.6 Hz, 1 H), 7.146 (s, 1 H), 6.792 (s, 1 H), 6.231 (d, J = 9.6 Hz, 1 H), 5.790 (m, 1H), 5.056-4.957 (m, 3H), 3.178 (dd, J = 4.8, 17.2 Hz, 1H), 2.837 (dd, J = 5.2, 17.2 Hz, 1H), 2.433 (m, 2H), 2.356 (t, J = 6.4 Hz, 2H), 1.374 (s, 3H), 1.352 (s, 3H);
MS(m/z) 329 (M+H)+.MS ( m / z ) 329 (M + H) + .
실시예 8. 아세트산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 8 Acetic Acid 2,2-Dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(8b)의 제조Preparation of Pyrano [3,2-g] chromen-3-yl-ester (8b)
(+)-데쿠르시놀(decursinol)과 라운드 플라스크에 1당량의 3-메틸-부-2-테노인산 대신 아세트산으로 바꾸는 점만 제외하고 상기 실시예 1의 반응과 동일한 반응 공정을 수행하여 하기 물성치를 갖는 아세트산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(8b)를 얻었다.The following physical properties were carried out in the same manner as in the reaction of Example 1, except that (+)-decursinol was changed to acetic acid instead of 1 equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask. An acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (8b) was obtained.
수율 : 89.8%;Yield: 89.8%;
고체상(Solid);Solid phase;
m.p 125-126℃;m.p 125-126 ° C .;
Rf=0.38(n-헥산:에틸아세테이트=1:1);R f = 0.38 (n-hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3, 400MHz): δppm 7.579(d, J=9.6Hz, 1H), 7.153(s, 1H), 6.791(s, 1H), 6.229(d, J=9.6Hz, 1H), 5.050(t, J=4.8Hz, 1H), 3.184(dd, J=4.0, 17.2Hz, 1H), 3.004(dd, J=4.8, 17.4Hz, 1H), 2.041(s, 3H), 1.422(s, 3H), 1.378(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.579 (d, J = 9.6 Hz, 1H), 7.153 (s, 1H), 6.791 (s, 1H), 6.229 (d, J = 9.6 Hz, 1H), 5.050 (t, J = 4.8 Hz, 1H), 3.184 (dd, J = 4.0, 17.2 Hz, 1H), 3.004 (dd, J = 4.8, 17.4 Hz, 1H), 2.041 (s, 3H), 1.422 (s, 3H), 1.378 (s, 3H);
MS(m/z) 289 (M+H)+.MS ( m / z ) 289 (M + H) + .
실시예 9. 클로로-아세트산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 9.Chloro-acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(9b)의 제조Preparation of Pyrano [3,2-g] chromen-3-yl-ester (9b)
(+)-데쿠르시놀(decursinol)과 라운드 플라스크에 1당량의 3-메틸-부-2-테노인산 대신 클로로-아세트산으로 바꾸는 점만 제외하고 상기 실시예 1의 반응과 동일한 반응 공정을 수행하여 하기 물성치를 갖는 클로로-아세트산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(9b)를 얻었다.The reaction process was carried out in the same manner as in Example 1, except that (+)-decursinol was replaced with chloro-acetic acid instead of 1 equivalent of 3-methyl-but-2-tenophosphoric acid in a round flask. Chloro-acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (9b) having the following physical properties was obtained. .
수율 : 96.2%;Yield: 96.2%;
고체상(Solid);Solid phase;
m.p 147-148℃;m.p 147-148 ° C .;
Rf=0.46(n-헥산:에틸아세테이트=1:1);R f = 0.46 (n-hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3, 400MHz): δppm 7.579(d, J=9.6Hz, 1H), 7.160(s, 1H), 6.794(s, 1H), 6.235(d, J=9.6Hz, 1H), 5.128(t, J=4.8Hz, 1H), 4.088(d, J= 14.8Hz, 1H), 4.031(d, J=14.8Hz, 1H), 3.229(dd, J=4.8, 17.2Hz, 1H), 2.907(dd, J=4.8, 17.2Hz, 1H), 1.400(s, 3H), 1.375(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.579 (d, J = 9.6 Hz, 1H), 7.160 (s, 1H), 6.794 (s, 1H), 6.235 (d, J = 9.6 Hz, 1H), 5.128 (t, J = 4.8 Hz, 1H), 4.088 (d, J = 14.8 Hz, 1H), 4.031 (d, J = 14.8 Hz, 1H), 3.229 (dd, J = 4.8, 17.2 Hz, 1H), 2.907 (dd, J = 4.8, 17.2 Hz, 1 H), 1.400 (s, 3 H), 1.375 (s, 3 H);
MS(m/z) 323 (M+H)+.MS ( m / z ) 323 (M + H) + .
실시예Example 10. 10. 트리클로로Trichloro -아세트산 2,2-디메틸-8-옥소-3,4-Acetic acid 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(10b)의 제조Preparation of 3-yl-ester (10b)
상기 반응식에서 나타난 바와 같이 (+)-데쿠르시놀(decursinol)을 무수 디클로로메탄으로 녹여 2당량의 피리딘(pyridine)과 2당량의 트리클로로아세틸 클로라이드(trichloro acetyl chloride, 10a)를 적가한 후, 실온에서 2시간 동안 교반하였다. 여액은 감압농축 하였으며, 순수한 생성물(10b)을 얻기 위해 농축액은 이동상(n-헥산 : 에틸아세테이드 = 10:1 ~ 3:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하여 하기 물성치를 갖는 트리클로로-아세트산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(10b)를 얻었다. As shown in the reaction scheme, (+)-decursinol was dissolved in anhydrous dichloromethane, and 2 equivalents of pyridine and 2 equivalents of trichloro acetyl chloride (10a) were added dropwise, followed by room temperature. Stirred for 2 h. The filtrate was concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 3: 1) to obtain a pure product (10b). Trichloro-acetic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (10b) was obtained.
수율 : 87.5%;Yield: 87.5%;
반고체상(Semi Solid);Semi Solid;
Rf=0.60(n-헥산:에틸아세테이트=1:1);R f = 0.60 (n-hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3, 400MHz): δppm 7.578(d, J=9.6Hz, 1H), 7.178(s, 1H), 6.185(s, 1H), 6.245(d, J=9.6Hz, 1H), 5.138(t, J=5.2Hz, 1H), 3.292(dd, J=4.8, 16.8Hz, 1H), 2.999 (dd, J=5.2, 17.2Hz, 1H), 1.450(s, 3H), 1.435(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.578 (d, J = 9.6 Hz, 1H), 7.178 (s, 1H), 6.185 (s, 1H), 6.245 (d, J = 9.6 Hz, 1H), 5.138 (t, J = 5.2 Hz, 1H), 3.292 (dd, J = 4.8, 16.8 Hz, 1H), 2.999 (dd, J = 5.2, 17.2 Hz, 1H), 1.450 (s, 3H), 1.435 (s, 3H);
MS(m/z) 392 (M+H)+.MS ( m / z ) 392 (M + H) + .
실시예Example 11. 11. 펜타노인산Pentanophosphate 2,2-디메틸-8-옥소-3,4- 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(11b)의 제조Preparation of 3-yl-ester (11b)
(+)-데쿠르시놀(decursinol)과 라운드 플라스크에 1당량의 트리클로로 아세틸 클로라이드 대신 펜타노일 클로라이드(pentanoyl chloride 혹은 valeroyl chloride)로 바꾸는 점만 제외하고 상기 실시예 10의 반응과 동일한 반응 공정을 수행하여 하기 물성치를 갖는 펜타노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(11b)를 얻었다.The reaction process was carried out in the same manner as in Example 10, except that (+)-decursinol was changed to pentanoyl chloride or valeroyl chloride instead of 1 equivalent of trichloro acetyl chloride in a round flask. Pentanophosphoric acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (11b) having the following physical properties was obtained. .
수율 : 90.7%;Yield: 90.7%;
오일상(Oil);Oil phase;
Rf=0.39(n-헥산:에틸아세테이트=2:1);R f = 0.39 (n-hexane: ethyl acetate = 2: 1);
1H NMR(CDCl3, 400MHz): δppm 7.576(d, J=9.6Hz, 1H), 7.145(s, 1H), 6.788(s, 1H), 6.224(d, J=9.6Hz, 1H), 5.044(t, J=5.2Hz, 1H), 3.180(dd, J=4.8, 16.8Hz, 1H), 2.837(dd, J=4.8, 16.8Hz, 1H), 2.313(t, J=7.6Hz, 2H), 1.580(m, 2H), 1.372(s, 3H), 1.355(s, 3H), 1.377-1.256(m, 2H), 0.876(t, J=7.2Hz, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.576 (d, J = 9.6 Hz, 1H), 7.145 (s, 1H), 6.788 (s, 1H), 6.224 (d, J = 9.6 Hz, 1H), 5.044 (t, J = 5.2 Hz, 1H), 3.180 (dd, J = 4.8, 16.8 Hz, 1H), 2.837 (dd, J = 4.8, 16.8 Hz, 1H), 2.313 (t, J = 7.6 Hz, 2H) , 1.580 (m, 2H), 1.372 (s, 3H), 1.355 (s, 3H), 1.377-1.256 (m, 2H), 0.876 (t, J = 7.2 Hz, 3H);
MS(m/z) 331 (M+H)+.MS ( m / z ) 331 (M + H) + .
실시예Example 12. 12. 데카노인산Decanoic acid 2,2-디메틸-8-옥소-3,4- 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(12b)의 제조Preparation of 3-yl-ester 12b
(+)-데쿠르시놀(decursinol)과 라운드 플라스크에 1당량의 트리클로로 아세틸 클로라이드 대신 데카노일 클로라이드(decanoyl chloride)로 바꾸는 점만 제외하고 상기 실시예 10의 반응과 동일한 반응 공정을 수행하여 하기 물성치를 갖는 데카노인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(12b)를 얻었다.The following physical properties were carried out in the same manner as in the reaction of Example 10, except that the decursinol and decursinol were changed to decanoyl chloride instead of 1 equivalent of trichloro acetyl chloride in a round flask. Decanoate 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (12b) having was obtained.
수율 : 93.0%;Yield: 93.0%;
오일상(Oil);Oil phase;
Rf=0.49(n-헥산:에틸아세테이트=2:1);R f = 0.49 (n-hexane: ethyl acetate = 2: 1);
1H NMR(CDCl3, 400MHz): δppm 7.574(d, J=9.2Hz, 1H), 7.143(s, 1H), 6.788(s, 1H), 6.227(d, J=9.2Hz, 1H), 5.043(t, J=4.8Hz, 1H), 3.178(dd, J=4.8, 16.8Hz, 1H), 2.839(dd, J=4.8, 17.2Hz, 1H), 2.323(t, J=8.0Hz, 2H), 1.615(m, 2H), 1.406(s, 3H), 1.373(s, 3H), 1.336-1.256(m, 12H), 0.888(t, J=7.2Hz, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.574 (d, J = 9.2 Hz, 1H), 7.143 (s, 1H), 6.788 (s, 1H), 6.227 (d, J = 9.2 Hz, 1H), 5.043 (t, J = 4.8 Hz, 1H), 3.178 (dd, J = 4.8, 16.8 Hz, 1H), 2.839 (dd, J = 4.8, 17.2 Hz, 1H), 2.323 (t, J = 8.0 Hz, 2H) , 1.615 (m, 2H), 1.406 (s, 3H), 1.373 (s, 3H), 1.336-1.256 (m, 12H), 0.888 (t, J = 7.2 Hz, 3H);
MS(m/z) 401 (M+H)+.MS ( m / z ) 401 (M + H) + .
실시예Example 13. 3- 13. 3- 페닐Phenyl -아크릴산 2,2-디메틸-8-옥소-3,4--Acrylic acid 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(13c)의 제조Preparation of 3-yl-ester (13c)
단계 2.Step 2.
상기 반응식에 나타난 바와 같이 1구 라운드 플라스크에 1.5 당량의 3-페닐-아크릴산을 넣고 이를 30-40당량의 무수 벤젠으로 용해하였다. 여기에 2 방울의 N,N-디메틸포름아마이드와 7.5당량의 티오닐클로라이드를 넣고 70-80℃에서 5시간 환류하였다. 이를 실온으로 냉각하여 감압농축 하였다. As shown in the reaction scheme, 1.5 equivalent of 3-phenyl-acrylic acid was added to a 1-neck round flask and dissolved in 30-40 equivalents of anhydrous benzene. Two drops of N, N -dimethylformamide and 7.5 equivalents of thionyl chloride were added thereto, and the mixture was refluxed at 70-80 ° C. for 5 hours. It was cooled to room temperature and concentrated under reduced pressure.
단계 3.Step 3.
1구 라운드 플라스크에 1당량의 (+)-데쿨시놀과 3당량의 피리딘을 넣고 50배(부피비)의 무수 디클로로메탄으로 용해하였다. 여기에 상기 제 1단계에서 반응한 1.5당량의 시나모일 클로라이드를 무수 디클로로메탄으로 용해하여 넣고, 실온에서 2시간 교반하였다. 이를 감압농축한 뒤 농축액은 이동상(n-헥산 : 에틸아세테이드 = 10:1 ~ 1:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하여 하기 물성치를 갖는 3-페닐-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(13c)를 얻었다.One equivalent of a round flask was charged with 1 equivalent of (+)-deculcinol and 3 equivalents of pyridine and dissolved in 50 times (volume ratio) of anhydrous dichloromethane. Herein, 1.5 equivalents of cinnamoyl chloride reacted in the first step was dissolved in anhydrous dichloromethane, and stirred at room temperature for 2 hours. After concentration under reduced pressure, the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1), and 3-phenyl-acrylic acid 2,2- having the following physical properties. Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (13c) was obtained.
수율 : 49.3%;Yield: 49.3%;
고체상(Solid);Solid phase;
m.p 136-137℃;m.p 136-137 ° C .;
Rf= 0.40(n-헥산:에틸아세테이트=1:1);R f = 0.40 (n-hexane: ethyl acetate = 1: 1);
1H NMR(acetone-d6, 400MHz): δ ppm 7.882(d, J=9.6Hz, 1H), 7.707(m, 3H), 7.433(m, 4H), 6.754(s, 1H), 6.568(d, J=16.0Hz, 1H), 6.212(d, J=9.2Hz, 1H), 5.240(t, J=4.6Hz, 1H), 3.344(dd, J=4.6, 17.6Hz, 1H), 2.991(dd, J=4.4, 17.6Hz, 1H), 1.436(s, 3H), 1.424(s, 3H); 1 H NMR (acetone-d 6 , 400 MHz): δ ppm 7.882 (d, J = 9.6 Hz, 1H), 7.707 (m, 3H), 7.433 (m, 4H), 6.754 (s, 1H), 6.568 (d , J = 16.0 Hz, 1H), 6.212 (d, J = 9.2 Hz, 1H), 5.240 (t, J = 4.6 Hz, 1H), 3.344 (dd, J = 4.6, 17.6 Hz, 1H), 2.991 (dd , J = 4.4, 17.6 Hz, 1H), 1.436 (s, 3H), 1.424 (s, 3H);
MS(m/z) 377 (M+H)+.MS ( m / z ) 377 (M + H) + .
실시예 14. 3-(3-하이드록시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 14. 3- (3-hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(14c)의 제조Preparation of Pyrano [3,2-g] chromen-3-yl-ester (14c)
단계 1.Step 1.
상기 실시예 13의 반응식에서 나타난 바와 같이 1구 라운드 플라스크에 10당량의 아세트산 무수물을 넣고 1당량의 3-(3-하이드록시-페닐)-아크릴산과 10당량의 피리딘을 첨가하였다. 이를 자석교반기에서 하룻동안 교반한 뒤, 감압농축 하였다. 농축액은 이동상(n-헥산 : 에틸아세테이드 = 5:1 ~ 1:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하였으며, 순수한 생성물을 얻었다. As shown in the reaction scheme of Example 13, 10 equivalents of acetic anhydride was added to a 1-neck round flask, and 1 equivalent of 3- (3-hydroxy-phenyl) -acrylic acid and 10 equivalents of pyridine were added. After stirring for one day in a magnetic stirrer, it was concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 5: 1 ~ 1: 1) to obtain a pure product.
단계 2Step 2
1구 라운드 플라스크에 1.5당량의 3-(3-아세톡시-페닐)-아크릴산을 넣고 이를 30-40당량의 무수 벤젠으로 용해하였다. 여기에 2 방울의 N,N-디메틸포름아마이드와 7.5당량의 티오닐클로라이드를 넣고 70-80도에서 5시간 환류하였다. 이를 실온으로 냉각하여 감압농축 하였다. 1.5 equivalent of 3- (3-acetoxy-phenyl) -acrylic acid was added to a 1-neck round flask and dissolved in 30-40 equivalents of anhydrous benzene. Two drops of N, N -dimethylformamide and 7.5 equivalents of thionyl chloride were added thereto, and the mixture was refluxed at 70-80 degrees for 5 hours. It was cooled to room temperature and concentrated under reduced pressure.
단계 3. Step 3.
1구 라운드 플라스크에 1당량의 (+)-데쿨시놀과 3당량의 피리딘을 넣고 50배(부피비)의 무수 디클로로메탄으로 용해하였다. 여기에 상기 제 2단계에서 반응한 1.5당량의 3-(3-아세톡시-페닐)-아크릴로일 클로라이드를 무수 디클로로메탄으로 용해하여 넣고, 실온에서 2시간 교반하였다. 이를 감압농축한 뒤 농축액은 이동상(n-헥산 : 에틸아세테이드 = 10:1 ~ 1:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하였으며, 순수한 생성물 3-(3-아세톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터를 얻었다.One equivalent of a round flask was charged with 1 equivalent of (+)-deculcinol and 3 equivalents of pyridine and dissolved in 50 times (volume ratio) of anhydrous dichloromethane. 1.5 equivalent of 3- (3-acetoxy-phenyl) -acryloyl chloride reacted in the second step was dissolved in anhydrous dichloromethane and stirred at room temperature for 2 hours. After concentration under reduced pressure, the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1), and the pure product 3- (3-acetoxy-phenyl). 2,2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester was obtained.
단계 4.Step 4.
상기 제 3단계에서 합성한 3-(3-아세톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터 1당량을 아세톤에 용해한 후, 4-8당량의 3N HCl을 적가하였다. 이를 50-60도에서 12시간 환류시킨 후, 실온으로 냉각하여 감압농축 하였다. 농축액은 에틸아세테이트와 증류수에 녹여 분액하였으며, 에틸아세테이트 층을 모아 무수망초로 탈수 후 여과하여 감압농축하였다. 농축액은 이동상(n-헥산 : 에틸아세테이드 = 5:1 ~ 2:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하여 하기 물성치를 갖는 3-(3-하이드록시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(14c)를 얻었다. 3- (3-acetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] black synthesized in the third step One equivalent of Men-3-yl-ester was dissolved in acetone, and then 4-8 equivalents of 3N HCl was added dropwise. It was refluxed at 50-60 degrees for 12 hours, and then cooled to room temperature and concentrated under reduced pressure. The concentrated solution was dissolved in ethyl acetate and distilled water and separated. The ethyl acetate layers were collected, dehydrated with anhydrous forget-me-not, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 5: 1 to 2: 1) to have 3- (3-hydroxy-phenyl) -acrylic acid 2, having the following physical properties. 2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (14c) was obtained.
수율 : 88.1% ;Yield: 88.1%;
고체상(Solid);Solid phase;
m.p 105℃;m.p 105 ° C .;
Rf= 0.21(n-헥산:에틸아세테이트=1:1);R f = 0.21 (n-hexane: ethyl acetate = 1: 1);
1H NMR(acetone-d6, 400MHz): δppm 7.863(d, J=9.2Hz, 1H), 7.622(d, J=15.6Hz, 1H), 7.442(s, 1H), 7.252(t, J=7.8Hz, 1H), 7.168(d, J=7.6Hz, 1H), 7.111(s, 1H), 6.915(d, J=8.4Hz, 1H), 6.751(s, 1H), 6.489(d, J=16.0Hz, 1H), 6.213(d, J=9.6Hz, 1H), 5.229(t, J=4.6Hz, 1H), 3.337(dd, J=4.2, 17.2Hz, 1H), 2.987(dd, J=4.4, 17.6Hz, 1H), 1.432(s, 3H), 1.422(s, 3H); 1 H NMR (acetone-d 6 , 400 MHz): δ ppm 7.863 (d, J = 9.2 Hz, 1H), 7.622 (d, J = 15.6 Hz, 1H), 7.442 (s, 1H), 7.252 (t, J = 7.8 Hz, 1H), 7.168 (d, J = 7.6 Hz, 1H), 7.111 (s, 1H), 6.915 (d, J = 8.4 Hz, 1H), 6.751 (s, 1H), 6.489 (d, J = 16.0 Hz, 1H), 6.213 (d, J = 9.6 Hz, 1H), 5.229 (t, J = 4.6 Hz, 1H), 3.337 (dd, J = 4.2, 17.2 Hz, 1H), 2.987 (dd, J = 4.4, 17.6 Hz, 1 H), 1.432 (s, 3 H), 1.422 (s, 3 H);
MS(m/z) 393 (M+H)+.MS ( m / z ) 393 (M + H) + .
실시예Example 15. 3-(3- 15. 3- (3- 아세톡시Acetoxy -- 페닐Phenyl )-아크릴산 2,2-디메틸-8-옥소-3,4-) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(15c)의 제조Preparation of 3-yl-ester (15c)
단계 1.Step 1.
상기 실시예 13의 반응식에서 나타난 바와 같이 1구 라운드 플라스크에 10당량의 아세트산 무수물을 넣고 1당량의 3-(3-하이드록시-페닐)-아크릴산과 10당량의 피리딘을 첨가하였다. 이를 자석교반기에서 하룻동안 교반한 뒤, 감압농축 하였다. 농축액은 이동상(n-헥산 : 에틸아세테이드 = 5:1 ~ 1:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하였으며, 순수한 생성물을 얻었다. As shown in the reaction scheme of Example 13, 10 equivalents of acetic anhydride was added to a 1-neck round flask, and 1 equivalent of 3- (3-hydroxy-phenyl) -acrylic acid and 10 equivalents of pyridine were added. After stirring for one day in a magnetic stirrer, it was concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 5: 1 ~ 1: 1) to obtain a pure product.
단계 2.Step 2.
1구 라운드 플라스크에 1.5당량의 3-(3-아세톡시-페닐)-아크릴산을 넣고 이를 30-40당량의 무수 벤젠으로 용해하였다. 여기에 2 방울의 N,N-디메틸포름아마이드와 7.5당량의 티오닐클로라이드를 넣고 70-80℃에서 5시간 환류하였다. 이를 실온으로 냉각하여 감압농축 하였다.1.5 equivalent of 3- (3-acetoxy-phenyl) -acrylic acid was added to a 1-neck round flask and dissolved in 30-40 equivalents of anhydrous benzene. Two drops of N, N -dimethylformamide and 7.5 equivalents of thionyl chloride were added thereto, and the mixture was refluxed at 70-80 ° C. for 5 hours. It was cooled to room temperature and concentrated under reduced pressure.
단계 3. Step 3.
1구 라운드 플라스크에 1당량의 (+)-데쿨시놀과 3당량의 피리딘을 넣고 50배(부피비)의 무수 디클로로메탄으로 용해하였다. 여기에 상기 제 2단계에서 반응한 1.5당량의 3-(3-아세톡시-페닐)-아크릴로일 클로라이드를 무수 디클로로메탄으로 용해하여 넣고, 실온에서 2시간 교반하였다. 이를 감압농축한 뒤 농축액은 이동상(n-헥산 : 에틸아세테이드 = 10:1 ~ 1:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하여, 하기 물성치를 갖는 3-(3-아세톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(15c)를 얻었다.One equivalent of a round flask was charged with 1 equivalent of (+)-deculcinol and 3 equivalents of pyridine and dissolved in 50 times (volume ratio) of anhydrous dichloromethane. 1.5 equivalent of 3- (3-acetoxy-phenyl) -acryloyl chloride reacted in the second step was dissolved in anhydrous dichloromethane and stirred at room temperature for 2 hours. After concentration under reduced pressure, the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1), and 3- (3-acetoxy- having the following physical properties. Phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (15c) was obtained.
수율 : 87.0%;Yield: 87.0%;
고체상(Solid);Solid phase;
m.p 181℃;m.p 181 ° C .;
Rf= 0.31(n-헥산:에틸아세테이트=1:1);R f = 0.31 (n-hexane: ethyl acetate = 1: 1);
1H NMR(acetone-d6, 400MHz): δ ppm 7.840(d, J=9.6Hz, 1H), 7.684(d, J=16.0Hz, 1H), 7.558(d, J=7.6Hz, 1H), 7.451(m, 3H), 7.180(dd, J=2.4, 7.6Hz, 1H), 6.737(s, 1H), 6.574(d, J=15.6Hz, 1H), 6.198(d, J=9.6Hz, 1H), 5.232(t, J=4.4Hz, 1H), 3.336(dd, J=4.2, 17.6Hz, 1H), 2.984(dd, J=4.8, 17.6Hz, 1H), 2.258(s, 3H), 1.430(s, 3H), 1.422(s, 3H); 1 H NMR (acetone-d 6 , 400 MHz): δ ppm 7.840 (d, J = 9.6 Hz, 1H), 7.684 (d, J = 16.0 Hz, 1H), 7.558 (d, J = 7.6 Hz, 1H), 7.451 (m, 3H), 7.180 (dd, J = 2.4, 7.6 Hz, 1H), 6.737 (s, 1H), 6.574 (d, J = 15.6 Hz, 1H), 6.198 (d, J = 9.6 Hz, 1H ), 5.232 (t, J = 4.4 Hz, 1H), 3.336 (dd, J = 4.2, 17.6 Hz, 1H), 2.984 (dd, J = 4.8, 17.6 Hz, 1H), 2.258 (s, 3H), 1.430 (s, 3H), 1. 422 (s, 3H);
MS(m/z) 435 (M+H)+.MS ( m / z ) 435 (M + H) + .
실시예Example 16. 3-(3,4-디히드록시- 16. 3- (3,4-dihydroxy- 페닐Phenyl )-아크릴산 2,2-디메틸-8-옥소-3,4-) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(16c)의 제조Preparation of 3-yl-ester 16c
상기 실시예 14의 제 1단계에서 1구 라운드 플라스크에 10당량의 아세트산 무수물을 넣고 1당량의 3-(3-히드록시-페닐)-아크릴산 대신 3-(3,4-디히드록시-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 14와 동일한 공정을 수행하여 하기 물성치를 갖는 3-(3,4-디히드록시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디히드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(16c)를 얻었다.In the first step of Example 14, 10 equivalents of acetic anhydride was added to a 1-neck round flask and 3- (3,4-dihydroxy-phenyl) instead of 1 equivalent of 3- (3-hydroxy-phenyl) -acrylic acid. Except for changing to acrylic acid, the same process as in Example 14 was carried out to give 3- (3,4-dihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-di having the following physical properties; Hydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (16c) was obtained.
수율 : 93.2%;Yield 93.2%;
고체상(Solid);Solid phase;
m.p 115℃;m.p 115 ° C .;
Rf= 0.36(n-헥산:에틸아세테이트=1:2);R f = 0.36 (n-hexane: ethyl acetate = 1: 2);
1H NMR(CDCl3, 400MHz): δppm 7.618(d, J=8.8Hz, 1H), 7.549(d, J=16.0Hz, 1H), 7.181(s, 1H), 7.068(s, 1H), 6.948(dd, J=1.6, 8.4Hz, 1H), 6.870(d, J=8.0Hz, 1H), 6.821(s, 1H), 6.223(m, 2H), 5.179(t, J=4.6Hz, 1H), 3.231(dd, J=4.6, 17.6Hz, 1H), 2.935(dd, J=4.6, 17.6Hz, 1H), 1.428(s, 3H), 1.379(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.618 (d, J = 8.8 Hz, 1H), 7.549 (d, J = 16.0 Hz, 1H), 7.181 (s, 1H), 7.068 (s, 1H), 6.948 (dd, J = 1.6, 8.4 Hz, 1H), 6.870 (d, J = 8.0 Hz, 1H), 6.821 (s, 1H), 6.223 (m, 2H), 5.179 (t, J = 4.6 Hz, 1H) , 3.231 (dd, J = 4.6, 17.6 Hz, 1H), 2.935 (dd, J = 4.6, 17.6 Hz, 1H), 1.428 (s, 3H), 1.379 (s, 3H);
MS(m/z) 409 (M+H)+.MS ( m / z ) 409 (M + H) + .
실시예Example 17. 3-(3,4- 17. 3- (3,4- 디아세톡시Diacetoxy -- 페닐Phenyl )-아크릴산 2,2-디메틸-8-옥소-3,4-) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(17c)의 제조Preparation of 3-yl-ester (17c)
상기 실시예 15의 제 1단계에서 1구 라운드 플라스크에 1당량의 3-(3-히드록시-페닐)-아크릴산 대신 3-(3,4-디히드록시-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 15와 동일한 공정을 수행하여 하기 물성치를 갖는 3-(3,4-다이아세톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(17c)를 얻었다.Except for changing the equivalent of 3- (3,4-dihydroxy-phenyl) -acrylic acid instead of one equivalent of 3- (3-hydroxy-phenyl) -acrylic acid in the first round flask of Example 15. 3- (3,4-Diacetoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -P having the same physical properties as in Example 15 was carried out. Llano [3,2-g] chromen-3-yl-ester (17c) was obtained.
수율 : 84.5%;Yield: 84.5%;
고체상(Solid);Solid phase;
m.p 92℃;m.p 92 ° C .;
Rf= 0.27(n-헥산:에틸아세테이트=1:1);R f = 0.27 (n-hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3, 400MHz): δ ppm 7.613(d, J=8.4Hz, 1H), 7.581(d, J=2.0Hz, 1H), 7.389-7.339(m, 2H), 7.256-7.179(m, 2H), 6.823(s, 1H), 6.358(d, J=16.0, 1H), 6.232(d, J=9.2Hz. 1H), 5.190(t, J=4.6Hz, 1H), 3.244(dd, J=4.6, 17.6Hz, 1H), 2.932(dd, J=4.6, 17.6Hz, 1H), 2.293(s, 3H), 2.290(s, 3H), 1.425(s, 3H), 1.389(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.613 (d, J = 8.4 Hz, 1H), 7.581 (d, J = 2.0 Hz, 1H), 7.389-7.339 (m, 2H), 7.256-7.179 (m , 2H), 6.823 (s, 1H), 6.358 (d, J = 16.0, 1H), 6.232 (d, J = 9.2 Hz. 1H), 5.190 (t, J = 4.6 Hz, 1H), 3.244 (dd, J = 4.6, 17.6 Hz, 1H), 2.932 (dd, J = 4.6, 17.6 Hz, 1H), 2.293 (s, 3H), 2.290 (s, 3H), 1.425 (s, 3H), 1.389 (s, 3H );
MS(m/z) 493 (M+H)+.MS ( m / z ) 493 (M + H) + .
실시예 18. 3-(4-히드록시-3-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 18. 3- (4-Hydroxy-3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(18c)의 제조Preparation of pyrano [3,2-g] chromen-3-yl-ester (18c)
상기 실시예 14의 제 1단계에서 1구 라운드 플라스크에 10당량의 아세트산 무수물을 넣고 1당량의 3-(3-히드록시-페닐)-아크릴산 대신 3-(4-하이드록시-3-메톡시-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 14와 동일한 공정을 수행하여 하기 물성치를 갖는 3-(4-히드록시-3-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(18c)를 얻었다.In the first step of Example 14, 10 equivalents of acetic anhydride was added to a 1-neck round flask and 3- (4-hydroxy-3-methoxy- instead of 1 equivalent of 3- (3-hydroxy-phenyl) -acrylic acid. Except for changing to phenyl) -acrylic acid, the same process as in Example 14 was carried out to provide 3- (4-hydroxy-3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3 having the following physical properties. , 4-Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (18c) was obtained.
수율 : 91.8% ;Yield: 91.8%;
고체상(Solid);Solid phase;
m.p 102℃;m.p 102 ° C .;
Rf= 0.32(n-헥산:에틸아세테이트=1:1);R f = 0.32 (n-hexane: ethyl acetate = 1: 1);
1H NMR(acetone-d6, 400MHz): δ ppm 7.843(d, J=9.6Hz, 1H), 7.616(d, J=16.0Hz, 1H), 7.424(s, 1H), 7.357(s, 1H), 7.123(dd, J=2.0, 8.0Hz, 1H), 6.851(d, J=8.4Hz, 1H), 6.740(s, 1H), 6.387(d, J=15.6Hz, 1H), 6.198(d, J=9.6Hz, 1H), 5.221(t, J=4.6Hz, 1H), 3.895(s, 3H), 3.321(dd, J=4.6, 17.2Hz, 1H), 2.963(dd, J=4.4, 17.6Hz, 1H), 1.421(s, 3H), 1.413(s, 3H); 1 H NMR (acetone-d 6 , 400 MHz): δ ppm 7.843 (d, J = 9.6 Hz, 1H), 7.616 (d, J = 16.0 Hz, 1H), 7.424 (s, 1H), 7.357 (s, 1H ), 7.123 (dd, J = 2.0, 8.0 Hz, 1H), 6.851 (d, J = 8.4 Hz, 1H), 6.740 (s, 1H), 6.387 (d, J = 15.6 Hz, 1H), 6.198 (d , J = 9.6 Hz, 1H), 5.221 (t, J = 4.6 Hz, 1H), 3.895 (s, 3H), 3.321 (dd, J = 4.6, 17.2 Hz, 1H), 2.963 (dd, J = 4.4, 17.6 Hz, 1H), 1.421 (s, 3H), 1.413 (s, 3H);
MS(m/z) 423 (M+H)+.MS ( m / z ) 423 (M + H) + .
실시예Example 19. 3-(4- 19. 3- (4- 아세톡시Acetoxy -3--3- 메톡시Methoxy -- 페닐Phenyl )-아크릴산 2,2-디메틸-8-옥소-3,4-) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(19c)의 제조Preparation of 3-yl-ester (19c)
상기 실시예 15의 제 1단계에서 1구 라운드 플라스크에 1당량의 3-(3-히드록시-페닐)-아크릴산 대신 3-(4-히드록시-3-메톡시-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 15와 동일한 공정을 수행하여 하기 물성치를 갖는 3-(4-아세톡시-3-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(19c)를 얻었다. In the first step of Example 15, only one equivalent of 3- (3-hydroxy-3-methoxy-phenyl) -acrylic acid was replaced with one equivalent of 3- (3-hydroxy-3-phenyl) -acrylic acid in a one-neck round flask. The procedure of Example 15 was repeated except that 3- (4-acetoxy-3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H having the following physical properties , 8H -pyrano [3,2-g] chromen-3-yl-ester (19c) was obtained.
수율 : 42.4% ;Yield: 42.4%;
고체(Solid);Solid;
m.p 98℃;m.p 98 ° C .;
Rf= 0.40(n-헥산:에틸아세테이트=1:1);R f = 0.40 (n-hexane: ethyl acetate = 1: 1);
1H NMR(acetone-d6, 400MHz): δppm 7.843(d, J=9.6Hz, 1H), 7.679(d, J=16.0Hz, 1H), 7.480(s, 1H), 7.428(s, 1H), 7.247(d, J=8.4Hz, 1H), 7.095(d, J=8.4Hz, 1H), 6.742(s, 1H), 6.568(d, J=16.0Hz, 1H), 6.200(d, J=9.6Hz, 1H), 5.243(t, J=4.4Hz, 1H), 3.872(s, 3H), 3.338(dd, J=4.4, 17.6Hz, 1H), 2.982(dd, J=4.4, 17.6, 1H), 2.242(s, 3H), 1.428(s, 3H), 1.418(s, 3H); 1 H NMR (acetone-d 6 , 400 MHz): δ ppm 7.843 (d, J = 9.6 Hz, 1H), 7.679 (d, J = 16.0 Hz, 1H), 7.480 (s, 1H), 7.428 (s, 1H) , 7.247 (d, J = 8.4 Hz, 1H), 7.095 (d, J = 8.4 Hz, 1H), 6.742 (s, 1H), 6.568 (d, J = 16.0 Hz, 1H), 6.200 (d, J = 9.6 Hz, 1H), 5.243 (t, J = 4.4 Hz, 1H), 3.872 (s, 3H), 3.338 (dd, J = 4.4, 17.6 Hz, 1H), 2.982 (dd, J = 4.4, 17.6, 1H ), 2.242 (s, 3H), 1.428 (s, 3H), 1.418 (s, 3H);
MS(m/z) 465 (M+H)+.MS ( m / z ) 465 (M + H) + .
실시예 20. 3-(4-아세톡시-3,5-디메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 20. 3- (4-Acetoxy-3,5-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(21c)의 제조Preparation of pyrano [3,2-g] chromen-3-yl-ester (21c)
상기 실시예 15의 제 1단계에서 1구 라운드 플라스크에 1당량의 3-(3-히드록시-페닐)-아크릴산 대신 3-(4-히드록시-3,5-디메톡시-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 15와 동일한 공정을 수행하여 하기 물성치를 갖는 3-(4-아세톡시-3,5-디메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(21c)를 얻었다. In the first step of Example 15, a 1-neck round flask was replaced with 3- (4-hydroxy-3,5-dimethoxy-phenyl) -acrylic acid instead of 1 equivalent of 3- (3-hydroxy-phenyl) -acrylic acid. A 3- (4-acetoxy-3,5-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4- having the following physical properties was carried out in the same manner as in Example 15 except for the change. Dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (21c) was obtained.
수율 : 10.8% ; Yield: 10.8%;
고체(Solid);Solid;
m.p 121℃;m.p 121 ° C .;
Rf= 0.42(n-hexane:ethyl acetate=1:1);R f = 0.42 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3): δppm 7.614(d, J=9.2Hz, 1H), 7.582(d, J=2.4Hz, 1H), 7.189(s, 1H), 6.826(s, 1H), 6.739(s, 2H), 6.362(d, J=16.0Hz, 1H), 6.227(d, J=9.2Hz, 1H), 5.211(t, J=4.8Hz, 1H), 3.801(s, 6H), 3.255(dd, J=4.8, 18.0Hz, 1H), 2.935(dd, J=4.8, 18.0Hz, 1H), 2.331(s, 3H), 1.451(s, 3H), 1.397(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.614 (d, J = 9.2 Hz, 1H), 7.582 (d, J = 2.4 Hz, 1H), 7.189 (s, 1H), 6.826 (s, 1H), 6.739 (s , 2H), 6.362 (d, J = 16.0 Hz, 1H), 6.227 (d, J = 9.2 Hz, 1H), 5.211 (t, J = 4.8 Hz, 1H), 3.801 (s, 6H), 3.255 (dd , J = 4.8, 18.0 Hz, 1H), 2.935 (dd, J = 4.8, 18.0 Hz, 1H), 2.331 (s, 3H), 1.451 (s, 3H), 1.397 (s, 3H);
MS(m/z) 495 (M+H)+.MS ( m / z ) 495 (M + H) + .
실시예Example 21. 3-(4- 21. 3- (4- 메톡시Methoxy -- 페닐Phenyl )-아크릴산 2,2-디메틸-8-옥소-3,4-) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -피-blood 라노[3,2-g]Lanolin [3,2-g] 크로멘-3-일-에스터(22c)Chromen-3-yl-ester (22c)
단계 1.Step 1.
상기 반응식에 나타난 바와 같이 1구 라운드 플라스크에 1.5당량의 3-(4-메톡시-페닐)-아크릴산을 넣고 이를 30-40당량의 무수 벤젠으로 용해하였다. 여기에 2 방울의 N,N-디메틸포름아마이드와 7.5당량의 티오닐클로라이드를 넣고 70-80℃에서 5시간 환류하였다. 이를 실온으로 냉각하여 감압농축 하였다. As shown in the reaction scheme, 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid was added to a 1-neck round flask and dissolved in 30-40 equivalents of anhydrous benzene. Two drops of N, N -dimethylformamide and 7.5 equivalents of thionyl chloride were added thereto, and the mixture was refluxed at 70-80 ° C. for 5 hours. It was cooled to room temperature and concentrated under reduced pressure.
단계 2. Step 2.
1구 라운드 플라스크에 1당량의 (+)-데쿨시놀과 3당량의 피리딘을 넣고 50배(부피비)의 무수 디클로로메탄으로 용해하였다. 여기에 상기 제 1단계에서 반응한 1.5당량의 3-(4-메톡시-페닐)-아크릴로일 클로라이드를 무수 디클로로메탄으로 용해하여 넣고, 실온에서 2시간 교반하였다. 이를 감압농축한 뒤 농축액은 이동상(n-헥산 : 에틸아세테이드 = 10:1 ~ 1:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하여, 하기 물성치를 갖는 3-(4-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(22c)를 얻었다. One equivalent of a round flask was charged with 1 equivalent of (+)-deculcinol and 3 equivalents of pyridine and dissolved in 50 times (volume ratio) of anhydrous dichloromethane. 1.5 equivalent of 3- (4-methoxy-phenyl) -acryloyl chloride reacted in the first step was dissolved in anhydrous dichloromethane and stirred at room temperature for 2 hours. After concentration under reduced pressure, the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1), and 3- (4-methoxy-) having the following physical properties. Phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (22c) was obtained.
수율 : 91.2%;Yield: 91.2%;
고체상(Solid);Solid phase;
m.p 68℃;m.p 68 ° C .;
Rf= 0.20(n-헥산:에틸아세테이트=2:1);R f = 0.20 (n-hexane: ethyl acetate = 2: 1);
1H NMR(CDCl3, 400MHz): δppm 7.631(d, J=16.0Hz, 1H), 7.583(d, J=9.2Hz, 1H), 7.450(d, J=8.4Hz, 1H), 7.170(s, 1H), 6.882(d, J=8.8Hz, 2H), 6.829(s, 1H), 6.282(d, J=16.0Hz, 1H), 6.231(d, J=9.2Hz, 1H), 5.188(t, J=4.8Hz, 1H), 3.828(s, 3H), 3.238(dd, J=4.4, 17.6Hz, 1H), 2.934(dd, J=4.4, 17.6Hz, 1H), 1.433(s, 3H), 1.391(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.631 (d, J = 16.0 Hz, 1H), 7.583 (d, J = 9.2 Hz, 1H), 7.450 (d, J = 8.4 Hz, 1H), 7.170 (s , 1H), 6.882 (d, J = 8.8 Hz, 2H), 6.829 (s, 1H), 6.282 (d, J = 16.0 Hz, 1H), 6.231 (d, J = 9.2 Hz, 1H), 5.188 (t , J = 4.8 Hz, 1H), 3.828 (s, 3H), 3.238 (dd, J = 4.4, 17.6 Hz, 1H), 2.934 (dd, J = 4.4, 17.6 Hz, 1H), 1.433 (s, 3H) , 1.391 (s, 3 H);
MS(m/z) 407 (M+H)+ . MS ( m / z ) 407 (M + H) + .
실시예Example 22. 3-(4-히드록시- 22. 3- (4-hydroxy- 페닐Phenyl )-아크릴산 2,2-디메틸-8-옥소-3,4-) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -피-blood 라노[3,2-g]Lanolin [3,2-g] 크로멘-3-일-에스터(22d)의 제조Preparation of Chromen-3-yl-ester (22d)
1구 라운드 플라스크에 1당량의 3-(4-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(22c)를 넣고 무수 디클로로메탄으로 녹인 후, 5당량의 1M 보론 트리브로마이드 용액(1M BBr3 in MC)을 적가한 후, 실온에서 2시간 동안 교반하였다. 반응혼액을 얼음물에 붓고 10분간 교반 후 에틸 아세테이트로 추출하였으며, 이를 무수망초로 탈수 후 감압농축 하였다. 농축액은 이동상(n-헥산 : 에틸아세테이드 = 10:1 ~ 1:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하여, 하기 물성치를 갖는 3-(4-히드록시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(22d)를 얻었다. One equivalent of a round flask with 1 equivalent of 3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] Chromium-3-yl-ester (22c) was added thereto, dissolved in anhydrous dichloromethane, and 5 equivalents of 1M boron tribromide solution (1M BBr 3 in MC) was added dropwise, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into iced water, stirred for 10 minutes and extracted with ethyl acetate, which was dehydrated with anhydrous forget-me-not and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1), and 3- (4-hydroxy-phenyl) -acrylic acid 2 having the following physical properties. , 2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (22d) was obtained.
수율 : 82.3%;Yield: 82.3%;
고체상(Solid);Solid phase;
m.p 104℃;m.p 104 ° C .;
Rf= 0.32(n-hexane:ethyl acetate=1:1);R f = 0.32 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3): δppm 7.608(m, 2H), 7.401(d, J=8.8Hz, 2H), 7.174(s, 1H), 6.841(m, 2H), 6.252(m, 2H), 5.825(s, OH), 5.187(t, J=4.6Hz, 1H), 3.237(dd, J=4.6, 17.6Hz, 1H), 2.935(dd, J=4.6, 17.6Hz, 1H), 1.432(s, 3H), 1.387(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.608 (m, 2H), 7.401 (d, J = 8.8 Hz, 2H), 7.174 (s, 1H), 6.841 (m, 2H), 6.252 (m, 2H), 5.825 (s, OH), 5.187 ( t, J = 4.6Hz, 1H), 3.237 (dd, J = 4.6, 17.6Hz, 1H), 2.935 (dd, J = 4.6, 17.6Hz, 1H), 1.432 (s, 3H), 1.387 (s, 3H);
MS(m/z) 393 (M+H)+ . MS ( m / z ) 393 (M + H) + .
실시예Example 23. 3-(3,4- 23. 3- (3,4- 디메톡시Dimethoxy -- 페닐Phenyl )-)- 아크릴산2Acrylic acid 2 ,2-디메틸-8-옥소-3,4-, 2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -피-blood 라노[3,2-g]Lanolin [3,2-g] 크로멘-3-일-에스터(23c)의 제조Preparation of Chromen-3-yl-ester (23c)
상기 실시예 21의 제 1단계에서 1구 라운드 플라스크에 1.5당량의 3-(4-메톡시-페닐)-아크릴산 대신 3-(3,4-디메톡시-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 21과 동일한 공정을 수행하여 하기 물성치를 갖는 3-(3,4-디메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(23c)를 얻었다. In the first step of Example 21, except that the 1-neck round flask was replaced with 3- (3,4-dimethoxy-phenyl) -acrylic acid instead of 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid. The process of Example 21 was carried out to give 3- (3,4-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [ 3,2-g] chromen-3-yl-ester (23c) was obtained.
수율 : 45.8%Yield: 45.8%
고체상(Solid);Solid phase;
m.p 83℃;m.p 83 ° C .;
Rf= 0.35(n-hexane:ethyl acetate=11);R f = 0.35 ( n- hexane: ethyl acetate = 11);
1H NMR(CDCl3): δppm 7.608(m, 2H), 7.178(s, 1H), 7.080(dd, J=8.4, 2.0Hz, 1H), 7.016(d, J=2.0Hz, 1H), 6.848(m, 2H), 6.256(dd, J=14.4, 9.6Hz, 2H), 5.200(t, J=4.4Hz, 1H), 3.916(s, 3H), 3.908(s, 3H), 3.230(dd, J=4.4, 16.8Hz, 1H), 2.965(dd, J=4.4, 16.8Hz, 1H), 1.446(s, 3H), 1.392(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.608 (m, 2H), 7.178 (s, 1H), 7.080 (dd, J = 8.4, 2.0 Hz, 1H), 7.016 (d, J = 2.0 Hz, 1H), 6.848 (m, 2H), 6.256 (dd, J = 14.4, 9.6 Hz, 2H), 5.200 (t, J = 4.4 Hz, 1H), 3.916 (s, 3H), 3.908 (s, 3H), 3.230 (dd, J = 4.4, 16.8 Hz, 1H), 2.965 (dd, J = 4.4, 16.8 Hz, 1H), 1.446 (s, 3H), 1.392 (s, 3H);
MS(m/z) 437 (M+H)+.MS ( m / z ) 437 (M + H) + .
실시예Example 24. 3-(3,4,5- 24. 3- (3,4,5- 트리메톡시Trimethoxy -- 페닐Phenyl )-아크릴산 2,2-디메틸-8-옥소-3,4-) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(24c)의 제조Preparation of 3-yl-ester 24c
상기 실시예 21의 제 1단계에서 1구 라운드 플라스크에 1.5당량의 3-(4-메톡시-페닐)-아크릴산 대신 3-(3,4,5-트리메톡시-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 21과 동일한 공정을 수행하여 하기 물성치를 갖는 3-(3,4,5-트리메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(24c)를 얻었다. In the first step of Example 21, only one point of the round flask was replaced with 3- (3,4,5-trimethoxy-phenyl) -acrylic acid instead of 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid. The procedure of Example 21 was repeated except that 3- (3,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H having the following physical properties , 8H -pyrano [3,2-g] chromen-3-yl-ester (24c) was obtained.
수율 : 52.9%;Yield: 52.9%;
고체상(Solid);Solid phase;
m.p 87℃;m.p 87 ° C .;
Rf= 0.23(n-hexane:ethyl acetate=1:1);R f = 0.23 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3): δppm 7.607(d, J=5.6Hz, 1H), 7.575(s, 1H), 7.184(s, 1H), 6.840(s, 1H), 6.722(s, 2H), 6.322(d, J=16.0Hz, 1H), 6.240(d, J=9.2Hz, 1H), 5.208(t, J=4.4Hz, 1H), 3.904(s, 9H), 3.254(dd, J=4.4, 16.8Hz, 1H), 2.951(dd, J=4.4, 16.8Hz, 1H), 1.452(s, 3H), 1.395(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.607 (d, J = 5.6 Hz, 1H), 7.575 (s, 1H), 7.184 (s, 1H), 6.840 (s, 1H), 6.722 (s, 2H), 6.322 (d, J = 16.0 Hz, 1H), 6.240 (d, J = 9.2 Hz, 1H), 5.208 (t, J = 4.4 Hz, 1H), 3.904 (s, 9H), 3.254 (dd, J = 4.4, 16.8 Hz, 1H), 2.951 (dd, J = 4.4, 16.8 Hz, 1H), 1.452 (s, 3H), 1.395 (s, 3H);
MS(m/z) 467 (M+H)+.MS ( m / z ) 467 (M + H) + .
실시예 25. 3-(3,4,5-트리히드록시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 25. 3- (3,4,5-Trihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(24d)의 제조Preparation of Pyrano [3,2-g] chromen-3-yl-ester (24d)
상기 실시예 22에서 1구 라운드 플라스크에 1당량의 3-(4-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(22c) 대신 3-(3,4,5-트리메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(24c)으로 바꾸는 점만 제외하고 실시예 22와 동일한 공정을 수행하여 하기 물성치를 갖는 3-(3,4,5-트리히드록시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(24d)를 얻었다. In Example 22, one equivalent of a round-necked flask, 1 equivalent of 3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3 3- (3,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro instead of, 2- g ] chromen-3-yl-ester (22c) The procedure of Example 22 was repeated except that the result was changed to 2H, 8H -pyrano [3,2- g ] chromen-3-yl-ester (24c), to give 3- (3,4, 5-Trihydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (24d )
수율 : 18.2%;Yield: 18.2%;
고체상(Solid);Solid phase;
m.p 144℃;m.p 144 ° C .;
Rf= 0.44(chloroform:methanol=5:1);R f = 0.44 (chloroform: methanol = 5: 1);
1H NMR(acetone-d6): δppm 7.849(d, J=9.6Hz, 1H), 7.453(m, 2H), 6.737(s, 1H), 6.720(s, 2H), 6.204(m, 2H), 5.195(t, J=4.8Hz, 1H), 3.310(dd, J=16.8, 4.8Hz, 1H), 2.937(dd, J=16.8, 4.8Hz, 1H), 1.417(s, 6H); 1 H NMR (acetone-d 6 ): δ ppm 7.849 (d, J = 9.6 Hz, 1H), 7.453 (m, 2H), 6.737 (s, 1H), 6.720 (s, 2H), 6.204 (m, 2H) 5.195 (t, J = 4.8 Hz, 1H), 3.310 (dd, J = 16.8, 4.8 Hz, 1H), 2.937 (dd, J = 16.8, 4.8 Hz, 1H), 1.417 (s, 6H);
MS(m/z) 425 (M+H)+.MS ( m / z ) 425 (M + H) + .
실시예 26. 3-(2-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 26. 3- (2-Methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(25c)의 제조Preparation of Pyrano [3,2-g] chromen-3-yl-ester (25c)
상기 실시예 21의 제 1단계에서 1구 라운드 플라스크에 1.5당량의 3-(4-메톡시-페닐)-아크릴산 대신 3-(2-메톡시-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 21과 동일한 공정을 수행하여 하기 물성치를 갖는 3-(2-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(25c)를 얻었다. Example 21 except that in the first step of Example 21, 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid was replaced with 3- (2-methoxy-phenyl) -acrylic acid in a one-neck round flask. 3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- having the following physical properties g] chromen-3-yl-ester (25c) was obtained.
수율 : 81.8%;Yield: 81.8%;
백색 고체상(Solid);White solid;
m.p 72℃;m.p 72 ° C .;
Rf= 0.48(n-hexane:ethyl acetate=1:1);R f = 0.48 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3): δppm 7.996(d, J=16.4Hz, 1H), 7.589(d, J=9.6Hz, 1H), 7.472(d, J=6.4Hz, 1H), 7.352(t, J=7.8Hz, 1H), 7.173(s, 1H), 6.960~6.895(m, 2H), 6.804(s, 1H), 6.508(d, J=16.0Hz, 1H), 6.235(d, J=9.6Hz, 1H), 5.194(t, J=5.0Hz, 1H), 3.871(s, 3H), 3.242(dd, J=5.0, 17.2Hz, 1H), 2.942(dd, J=5.0, 17.2Hz, 1H), 1.437(s, 3H), 1.396(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.996 (d, J = 16.4 Hz, 1H), 7.589 (d, J = 9.6 Hz, 1H), 7.472 (d, J = 6.4 Hz, 1H), 7.352 (t, J = 7.8 Hz, 1H), 7.173 (s, 1H), 6.960-6.895 (m, 2H), 6.804 (s, 1H), 6.508 (d, J = 16.0 Hz, 1H), 6.235 (d, J = 9.6 Hz , 1H), 5.194 (t, J = 5.0 Hz, 1H), 3.871 (s, 3H), 3.242 (dd, J = 5.0, 17.2 Hz, 1H), 2.942 (dd, J = 5.0, 17.2 Hz, 1H) , 1.437 (s, 3H), 1.396 (s, 3H);
MS(m/z) 407 (M+H)+.MS ( m / z ) 407 (M + H) + .
실시예 27. 3-(2-히드록시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 27. 3- (2-Hydroxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(25d)의 제조Preparation of Pyrano [3,2-g] chromen-3-yl-ester (25d)
상기 실시예 22에서 1구 라운드 플라스크에 1당량의 3-(4-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(22c) 대신 3-(2-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(25c)으로 바꾸는 점만 제외하고 실시예 22와 동일한 공정을 수행하여 하기 물성치를 갖는 3-(2-히드록시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(25d)를 얻었다. In Example 22, one equivalent of a round-necked flask, 1 equivalent of 3- (4-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3 3- (2-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H instead of, 2- g ] chromen-3-yl-ester (22c) The procedure of Example 22 was repeated except for changing to pyrano [3,2- g ] chromen-3-yl-ester (25c) to give 3- (2-hydroxy-phenyl) -acrylic acid having the following physical properties. 2,2-Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (25d) was obtained.
수율 : 58.5%;Yield: 58.5%;
백색 고체상(Solid);White solid;
m.p 106℃;m.p 106 ° C .;
Rf= 0.39(n-hexane:ethyl acetate=1:1);R f = 0.39 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(acetone-d6): δppm 8.001(d, J=16.4Hz, 1H), 7.851(d, J=9.2Hz, 1H), 7.613(d, J=7.6Hz, 1H), 7.434(s, 1H), 7.253(t, J=6.8Hz, 1H), 6.954(d, J=8.4Hz, 1H), 6.883(t, J=7.4Hz, 1H), 6.741(s, 1H), 6.614(d, J=16.0Hz, 1H), 6.203(d, J=9.6Hz, 1H), 5.233(t, J=4.4Hz, 1H), 3.332(dd, J=4.4, 17.6Hz, 1H), 2.984(dd, J=4.4, 17.6Hz, 1H), 2.913(d, J=12.0Hz, OH), 1.432(s, 3H), 1.421(s, 3H); 1 H NMR (acetone-d 6 ): δ ppm 8.001 (d, J = 16.4 Hz, 1H), 7.851 (d, J = 9.2 Hz, 1H), 7.613 (d, J = 7.6 Hz, 1H), 7.434 (s , 1H), 7.253 (t, J = 6.8 Hz, 1H), 6.954 (d, J = 8.4 Hz, 1H), 6.883 (t, J = 7.4 Hz, 1H), 6.741 (s, 1H), 6.614 (d , J = 16.0 Hz, 1H), 6.203 (d, J = 9.6 Hz, 1H), 5.233 (t, J = 4.4 Hz, 1H), 3.332 (dd, J = 4.4, 17.6 Hz, 1H), 2.984 (dd , J = 4.4, 17.6 Hz, 1H), 2.913 (d, J = 12.0 Hz, OH), 1.432 (s, 3H), 1.421 (s, 3H);
MS(m/z) 393 (M+H)+ .MS ( m / z ) 393 (M + H) + .
실시예 28. 3-(3-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 28. 3- (3-Methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(26c)의 제조Preparation of Pyrano [3,2-g] chromen-3-yl-ester (26c)
상기 실시예 21의 제 1단계에서 1구 라운드 플라스크에 1.5당량의 3-(4-메톡시-페닐)-아크릴산 대신 3-(3-메톡시-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 21과 동일한 공정을 수행하여 하기 물성치를 갖는 3-(3-메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(26c)를 얻었다. Example 21 except that in the first step of Example 21, 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid was replaced with 3- (3-methoxy-phenyl) -acrylic acid in a one-neck round flask. 3- (3-methoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2- having the following physical properties g] chromen-3-yl-ester (26c) was obtained.
수율 : 90.9%;Yield: 90.9%;
백색고체상(Solid);White solid;
m.p 72℃;m.p 72 ° C .;
Rf= 0.51(n-hexane:ethyl acetate=1:1);R f = 0.51 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3): δppm 7.644(d, J=16.0Hz, 1H), 7.584(d, J=9.6Hz, 1H), 7.282(t, J=8.4Hz, 1H), 7.175(s, 1H), 7.088(d, J=8.0Hz, 1H), 6.932(dd, J=4.0, 8.4Hz, 1H), 6.835(s, 1H), 6.403(d, J=15.6Hz, 1H), 6.236(d, J=9.6Hz, 1H), 5.199(t, J=4.8Hz, 1H), 3.813(s, 3H), 3.248(dd, J=4.8, 17.2Hz, 1H), 2.943(dd, J=4.8, 17.2Hz, 1H), 1.440(s, 3H), 1.394(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.644 (d, J = 16.0 Hz, 1H), 7.584 (d, J = 9.6 Hz, 1H), 7.282 (t, J = 8.4 Hz, 1H), 7.175 (s, 1H) ), 7.088 (d, J = 8.0 Hz, 1H), 6.932 (dd, J = 4.0, 8.4 Hz, 1H), 6.835 (s, 1H), 6.403 (d, J = 15.6 Hz, 1H), 6.236 (d , J = 9.6 Hz, 1H), 5.199 (t, J = 4.8 Hz, 1H), 3.813 (s, 3H), 3.248 (dd, J = 4.8, 17.2 Hz, 1H), 2.943 (dd, J = 4.8, 17.2 Hz, 1H), 1.440 (s, 3H), 1.394 (s, 3H);
MS(m/z) 407 (M+H)+.MS ( m / z ) 407 (M + H) + .
실시예 29. 3-(2,3-디메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 29. 3- (2,3-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(27c)의 제조Preparation of pyrano [3,2-g] chromen-3-yl-ester (27c)
상기 실시예 21의 제 1단계에서 1구 라운드 플라스크에 1.5당량의 3-(4-메톡시-페닐)-아크릴산 대신 3-(2,3-디메톡시-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 21과 동일한 공정을 수행하여 하기 물성치를 갖는 3-(2,3-디메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(27c)를 얻었다. In the first step of Example 21, except that the 1-neck round flask was replaced with 3- (2,3-dimethoxy-phenyl) -acrylic acid instead of 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid. The same process as in Example 21 was carried out to give 3- (2,3-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [ 3,2-g] chromen-3-yl-ester (27c) was obtained.
수율 : 25.0%;Yield: 25.0%;
백색 고체상(Solid);White solid;
m.p 149℃;m.p 149 ° C .;
Rf= 0.43(n-hexane:ethyl acetate=1:1);R f = 0.43 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3): δppm 8.021(d, J=16.0Hz, 1H), 7.585(d, J=9.6Hz,1H), 7.174(s, 1H), 7.121(d, J=6.8Hz, 1H), 7.032(t, J=8.0Hz, 1H), 6.939(d, J=8.8Hz, 1H), 6.829(s, 1H), 6.449(d, J=16.8Hz, 1H), 6.232(d, J=9.6Hz, 1H), 5.192(t, J=4.8Hz, 1H), 3.868(s, 3H), 3.832(s, 3H), 3.249(dd, J=4.8, 17.2Hz, 1H), 2.945(dd, J=4.8, 17.2Hz, 1H), 1.435(s, 3H), 1.400(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 8.021 (d, J = 16.0 Hz, 1H), 7.585 (d, J = 9.6 Hz, 1H), 7.174 (s, 1H), 7.121 (d, J = 6.8 Hz, 1H ), 7.032 (t, J = 8.0 Hz, 1H), 6.939 (d, J = 8.8 Hz, 1H), 6.829 (s, 1H), 6.449 (d, J = 16.8 Hz, 1H), 6.232 (d, J = 9.6 Hz, 1H), 5.192 (t, J = 4.8 Hz, 1H), 3.868 (s, 3H), 3.832 (s, 3H), 3.249 (dd, J = 4.8, 17.2 Hz, 1H), 2.945 (dd , J = 4.8, 17.2 Hz, 1H), 1.435 (s, 3H), 1.400 (s, 3H);
MS(m/z) 437 (M+H)+.MS ( m / z ) 437 (M + H) + .
실시예 30. 3-(2,4-디메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-Example 30. 3- (2,4-Dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H,8H2H, 8H -피라노[3,2-g]크로멘-3-일-에스터(28c)의 제조Preparation of Pyrano [3,2-g] chromen-3-yl-ester (28c)
상기 실시예 21의 제 1단계에서 1구 라운드 플라스크에 1.5당량의 3-(4-메톡시-페닐)-아크릴산 대신 3-(2,4-디메톡시-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 21과 동일한 공정을 수행하여 하기 물성치를 갖는 3-(2,4-디메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(28c)를 얻었다. In the first step of Example 21, except that the 1-neck round flask was replaced with 3- (2,4-dimethoxy-phenyl) -acrylic acid instead of 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid. The process of Example 21 was carried out to give 3- (2,4-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [ 3,2-g] chromen-3-yl-ester (28c) was obtained.
수율 : 25.0%;Yield: 25.0%;
백색 고체상(Solid);White solid;
m.p 149℃;m.p 149 ° C .;
Rf= 0.43(n-hexane:ethyl acetate=1:1);R f = 0.43 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3): δppm 8.021(d, J=16.0Hz, 1H), 7.585(d, J=9.6Hz,1H), 7.174(s, 1H), 7.121(d, J=6.8Hz, 1H), 7.032(t, J=8.0Hz, 1H), 6.939(d, J=8.8Hz, 1H), 6.829(s, 1H), 6.449(d, J=16.8Hz, 1H), 6.232(d, J=9.6Hz, 1H), 5.192(t, J=4.8Hz, 1H), 3.868(s, 3H), 3.832(s, 3H), 3.249(dd, J=4.8, 17.2Hz, 1H), 2.945(dd, J=4.8, 17.2Hz, 1H), 1.435(s, 3H), 1.400(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 8.021 (d, J = 16.0 Hz, 1H), 7.585 (d, J = 9.6 Hz, 1H), 7.174 (s, 1H), 7.121 (d, J = 6.8 Hz, 1H ), 7.032 (t, J = 8.0 Hz, 1H), 6.939 (d, J = 8.8 Hz, 1H), 6.829 (s, 1H), 6.449 (d, J = 16.8 Hz, 1H), 6.232 (d, J = 9.6 Hz, 1H), 5.192 (t, J = 4.8 Hz, 1H), 3.868 (s, 3H), 3.832 (s, 3H), 3.249 (dd, J = 4.8, 17.2 Hz, 1H), 2.945 (dd , J = 4.8, 17.2 Hz, 1H), 1.435 (s, 3H), 1.400 (s, 3H);
MS(m/z) 437 (M+H)+.MS ( m / z ) 437 (M + H) + .
실시예Example 31. 3-(2,5- 31. 3- (2,5- 디메톡시Dimethoxy -- 페닐Phenyl )-아크릴산 2,2-디메틸-8-옥소-3,4-) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(29c)의 제조Preparation of 3-yl-ester (29c)
상기 실시예 21의 제 1단계에서 1구 라운드 플라스크에 1.5당량의 3-(4-메톡시-페닐)-아크릴산 대신 3-(2,5-디메톡시-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 21과 동일한 공정을 수행하여 하기 물성치를 갖는 3-(2,5-디메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(29c)를 얻었다. Except for changing to 1.5 equivalent 3- (4-methoxy-phenyl) -acrylic acid instead of 3- (2,5-dimethoxy-phenyl) -acrylic acid in the first round flask in Example 21. The process of Example 21 was carried out to give 3- (2,5-dimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [ 3,2-g] chromen-3-yl-ester (29c) was obtained.
수율 : 38.7%;Yield: 38.7%;
연황색 고체상(Solid);Light yellow solid;
m.p 77℃;m.p 77 ° C .;
Rf= 0.46(n-hexane:ethyl acetate=1:1);R f = 0.46 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3): δppm 7.983(d, J=16.0Hz, 1H), 7.592(d, J=10.4Hz, 1H), 7.178(s, 1H), 7.001(d, J=2.8Hz, 1H), 6.912(dd, J=2.8, 8.8Hz, 1H), 6.849~6.827(m, 2H), 6.471(d, J=16.4Hz, 1H), 6.237(d, J=9.2Hz, 1H), 5.196(t, J=4.8Hz, 1H), 3.824(s, 3H), 3.768(s, 3H), 3.245(dd, J=4.8, 17.2Hz, 1H), 2.945(dd, J=4.8, 17.2Hz, 1H), 1.441(s, 3H), 1.396(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.983 (d, J = 16.0 Hz, 1H), 7.592 (d, J = 10.4 Hz, 1H), 7.178 (s, 1H), 7.001 (d, J = 2.8 Hz, 1H ), 6.912 (dd, J = 2.8, 8.8 Hz, 1H), 6.849-6.827 (m, 2H), 6.471 (d, J = 16.4 Hz, 1H), 6.237 (d, J = 9.2 Hz, 1H), 5.196 (t, J = 4.8 Hz, 1H), 3.824 (s, 3H), 3.768 (s, 3H), 3.245 (dd, J = 4.8, 17.2 Hz, 1H), 2.945 (dd, J = 4.8, 17.2 Hz, 1H), 1.441 (s, 3H), 1.396 (s, 3H);
MS(m/z) 437 (M+H)+.MS ( m / z ) 437 (M + H) + .
실시예Example 32. 3-(2,4,5- 32. 3- (2,4,5- 트리메톡시Trimethoxy -- 페닐Phenyl )-아크릴산 2,2-디메틸-8-옥소-3,4-) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(30c)의 제조Preparation of 3-yl-ester 30c
상기 실시예 21의 제 1단계에서 1구 라운드 플라스크에 1.5당량의 3-(4-메톡시-페닐)-아크릴산 대신 3-(2,4,5-트리메톡시-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 21과 동일한 공정을 수행하여 하기 물성치를 갖는 3-(2,4,5-트리메톡시-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(30c)를 얻었다. In the first step of Example 21, in the one-neck round flask, only 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid was replaced with 3- (2,4,5-trimethoxy-phenyl) -acrylic acid. The procedure of Example 21 was repeated except that 3- (2,4,5-trimethoxy-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H having the following physical properties , 8H -pyrano [3,2-g] chromen-3-yl-ester (30c) was obtained.
수율 : 33.5%;Yield: 33.5%;
황색 고체상(Solid);Yellow solid;
m.p 93℃;m.p 93 ° C .;
Rf= 0.29(n-hexane:ethyl acetate=1:1);R f = 0.29 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3): δppm 7.986(d, J=13.6Hz, 1H), 7.586(d, J=9.6Hz, 1H), 7.173(s, 1H), 6.966(s, 1H), 6.833(s, 1H), 6.478(s, 1H), 6.325(d, J=16.0Hz, 1H), 6.232(d, J=9.2Hz, 1H), 5.196(t, J=4.8Hz, 1H), 3.922(s, 3H), 3.855(s, 3H), 3.840(s, 3H), 3.238(dd, J=4.8, 17.2Hz, 1H), 2.940(dd, J=4.8, 17.2Hz, 1H), 1.443(s, 3H), 1.393(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.986 (d, J = 13.6 Hz, 1H), 7.586 (d, J = 9.6 Hz, 1H), 7.173 (s, 1H), 6.966 (s, 1H), 6.833 (s , 1H), 6.478 (s, 1H), 6.325 (d, J = 16.0 Hz, 1H), 6.232 (d, J = 9.2 Hz, 1H), 5.196 (t, J = 4.8 Hz, 1H), 3.922 (s , 3H), 3.855 (s, 3H), 3.840 (s, 3H), 3.238 (dd, J = 4.8, 17.2 Hz, 1H), 2.940 (dd, J = 4.8, 17.2 Hz, 1H), 1.443 (s, 3H), 1.393 (s, 3H);
MS(m/z) 483 (M+H)+.MS ( m / z ) 483 (M + H) + .
실시예Example 33. 3-(4-니트로- 33. 3- (4-nitro- 페닐Phenyl )-아크릴산 2,2-디메틸-8-옥소-3,4-) -Acrylic acid 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(31c)의 제조Preparation of 3-yl-ester 31c
상기 실시예 21의 제 1단계에서 1구 라운드 플라스크에 1.5당량의 3-(4-메톡시-페닐)-아크릴산 대신 3-(4-니트로-페닐)-아크릴산으로 바꾸는 점만 제외하고 실시예 21과 동일한 공정을 수행하여 하기 물성치를 갖는 3-(4-니트로-페닐)-아크릴산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(31c)를 얻었다. Example 21 and 1 except that in the first step of Example 21 was replaced with 3- (4-nitro-phenyl) -acrylic acid instead of 1.5 equivalent of 3- (4-methoxy-phenyl) -acrylic acid in a one-neck round flask 3- (4-nitro-phenyl) -acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] having the following physical properties by carrying out the same process Chromen-3-yl-ester (31c) was obtained.
수율 : 65.7%;Yield: 65.7%;
연황색 고체상(Solid);Light yellow solid;
m.p 193℃;m.p 193 ° C .;
Rf= 0.42(n-hexane:ethyl acetate=1:1);R f = 0.42 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3): δppm 8.237(d, J=8.8Hz, 2H), 7.727~7.623(m, 3H), 7.598(d, J=9.2Hz, 1H), 7.218(s, 1H), 6.840(s, 1H), 6.560(d, J=11.2Hz, 1H), 6.248(d, J=9.6Hz, 1H), 5.225(t, J=4.8Hz, 1H), 3.272(dd, J=4.8, 17.2Hz, 1H), 2.958(dd, J=4.8, 17.2Hz, 1H), 1.449(s, 3H), 1.403(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 8.237 (d, J = 8.8 Hz, 2H), 7.727-7.623 (m, 3H), 7.598 (d, J = 9.2 Hz, 1H), 7.218 (s, 1H), 6.840 (s, 1H), 6.560 (d, J = 11.2 Hz, 1H), 6.248 (d, J = 9.6 Hz, 1H), 5.225 (t, J = 4.8 Hz, 1H), 3.272 (dd, J = 4.8, 17.2 Hz, 1H), 2.958 (dd, J = 4.8, 17.2 Hz, 1H), 1.449 (s, 3H), 1.403 (s, 3H);
MS(m/z) 422 (M+H)+.MS ( m / z ) 422 (M + H) + .
실시예Example 34. 34. 벤조인산Benzoic acid 2,2-디메틸-8-옥소-3,4- 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(32c)의 제조Preparation of 3-yl-ester 32c
단계 2.Step 2.
상기 반응식에서와 같이 1구 라운드 플라스크에 1.5당량의 벤조인산을 넣고 이를 30-40당량의 무수 벤젠으로 용해하였다. 여기에 2 방울의 N,N-디메틸포름아마이드와 7.5당량의 티오닐 클로라이드를 넣고 70-80도에서 5시간 환류하였다. 이를 실온으로 냉각하여 감압농축 하였다. As in the reaction scheme, 1.5 equivalents of benzoic acid was added to a 1-neck round flask and dissolved in 30-40 equivalents of anhydrous benzene. Two drops of N, N -dimethylformamide and 7.5 equivalents of thionyl chloride were added thereto, and the mixture was refluxed at 70-80 degrees for 5 hours. It was cooled to room temperature and concentrated under reduced pressure.
단계 3. Step 3.
1구 라운드 플라스크에 1당량의 (+)-데쿠르시놀과 3당량의 피리딘을 넣고 50배(부피비)의 무수 디클로로메탄으로 용해하였다. 여기에 상기 제 2단계에서 합성한 벤조일 클로라이드를 무수 디클로로메탄에 용해하여 첨가하였으며, 실온에서 2시간 교반하였다. 이를 감압농축한 뒤 농축액은 이동상(n-헥산 : 에틸아세테이드 = 10:1 ~ 1:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하여, 순수한 생성물 벤조인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(32c)을 얻었다.One equivalent of a round flask was charged with 1 equivalent of (+)-decurinol and 3 equivalents of pyridine and dissolved in 50 times (volume ratio) of anhydrous dichloromethane. The benzoyl chloride synthesized in the second step was dissolved in anhydrous dichloromethane and added thereto, followed by stirring at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1 to 1: 1) to obtain pure product benzoic acid 2,2-dimethyl-8-. Oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (32c) was obtained.
수율 : 93.2% ;Yield 93.2%;
반고체상(Semi solid);Semi solid;
Rf=0.52(n-헥산:에틸아세테이트=1:1);R f = 0.52 (n-hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3, 400MHz): δ ppm 7.972(d, J=9.6Hz, 2H), 7.557(m, 2H), 7.417(t, J=7.8Hz, 2H), 7.166(s, 1H), 6.845(s, 1H), 6.227(d, J=9.6Hz, 1H), 5.296(t, J=4.8Hz, 1H), 3.300(dd, J=4.4, 17.6Hz, 1H), 3.004(dd, J=4.8, 17.6Hz, 1H), 1.474(s, 3H), 1.428(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.972 (d, J = 9.6 Hz, 2H), 7.557 (m, 2H), 7.417 (t, J = 7.8 Hz, 2H), 7.166 (s, 1H), 6.845 (s, 1H), 6.227 (d, J = 9.6 Hz, 1H), 5.296 (t, J = 4.8 Hz, 1H), 3.300 (dd, J = 4.4, 17.6 Hz, 1H), 3.004 (dd, J = 4.8, 17.6 Hz, 1H), 1.474 (s, 3H), 1.428 (s, 3H);
MS(m/z) 351 (M+H)+.MS ( m / z ) 351 (M + H) + .
실시예Example 35. 3,4,5- 35. 3,4,5- 트리히드록시Trihydroxy -- 벤조인산Benzoic acid 2,2-디메틸-8-옥소-3,4- 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(33c)의 제조Preparation of 3-yl-ester (33c)
단계 1.Step 1.
상기 실시예 34의 반응식에서 나타난 바와 같이 1구 라운드 플라스크에 10당량의 아세트산 무수물을 넣고 1당량의 3,4,5-트리히드록시 벤조인산과 10당량의 피리딘을 첨가하였다. 이를 자석교반기에서 하룻동안 교반한 뒤, 감압농축 하였다. 농축액은 이동상(n-헥산 : 에틸아세테이드 = 5:1 ~ 1:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하였으며, 순수한 생성물을 얻었다. As shown in the reaction scheme of Example 34, 10 equivalents of acetic anhydride was added to a 1-neck round flask, and 1 equivalent of 3,4,5-trihydroxy benzoic acid and 10 equivalents of pyridine were added thereto. After stirring for one day in a magnetic stirrer, it was concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 5: 1 ~ 1: 1) to obtain a pure product.
단계 2 및 단계 3Step 2 and Step 3
상기 실시예 34의 제 2단계에서 1구 라운드 플라스크에 1.5당량의 벤조인산대신 3,4,5-트리아세톡시 벤조인산으로 바꾸는 점만 제외하고 실시예 34의 제 2단계, 제 3단계와 동일한 공정을 수행하여, 순수한 생성물 3,4,5-트리아세톡시 벤조인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터를 얻었다.The same process as the second step and the third step of Example 34, except that the first round flask in Example 34 was replaced with 3,4,5-triacetoxy benzoic acid instead of 1.5 equivalents of benzoic acid. Pure product 3,4,5-triacetoxy benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen- 3-yl-ester was obtained.
단계 4.Step 4.
상기 제 2, 3단계에서 합성한 3,4,5-트리아세톡시 벤조인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터 1당량을 아세톤에 용해한 후, 4-8당량의 3N HCl을 적가하였다. 이를 50-60도에서 12시간 환류시킨 후, 실온으로 냉각하여 감압농축 하였다. 농축액은 에틸아세테이트와 증류수에 녹여 분액하였으며, 에틸아세테이트 층을 모아 무수망초로 탈수 후 여과하여 감압농축하였다. 농축액은 이동상(n-헥산 : 에틸아세테이드 = 5:1 ~ 2:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하여 하기 물성치를 갖는 3,4,5-트리히드록시 벤조인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(33c)를 얻었다. 3,4,5-triacetoxy benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] synthesized in steps 2 and 3 above One equivalent of chromen-3-yl-ester was dissolved in acetone, and then 4-8 equivalents of 3N HCl was added dropwise. It was refluxed at 50-60 degrees for 12 hours, and then cooled to room temperature and concentrated under reduced pressure. The concentrated solution was dissolved in ethyl acetate and distilled water and separated. The ethyl acetate layers were collected, dehydrated with anhydrous forget-me-not, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 5: 1 to 2: 1) to give 3,4,5-trihydroxy benzoic acid 2,2 having the following physical properties. -Dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen-3-yl-ester (33c) was obtained.
수율 : 98.7% ;Yield: 98.7%;
고체상(Solid);Solid phase;
m.p 138℃;m.p 138 ° C .;
Rf= 0.22(n-헥산:에틸아세테이트=1:2);R f = 0.22 (n-hexane: ethyl acetate = 1: 2);
1H NMR(CDCl3, 400MHz): δppm 7.674(d, J=9.2Hz, 1H), 7.242(s, 1H), 7.132(s, 2H), 6.782(s, 1H), 6.228(d, J=9.2Hz, 1H), 5.215(t, J=4.8Hz, 1H), 3.284(dd, J=4.2, 17.6Hz, 1H), 2.981(dd, J=4.6, 17.6Hz, 1H), 1.443(s, 3H), 1.413(s, 3H)3H) 1.292(s, 3H), 1.287(s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.674 (d, J = 9.2 Hz, 1H), 7.242 (s, 1H), 7.132 (s, 2H), 6.782 (s, 1H), 6.228 (d, J = 9.2 Hz, 1H), 5.215 (t, J = 4.8 Hz, 1H), 3.284 (dd, J = 4.2, 17.6 Hz, 1H), 2.981 (dd, J = 4.6, 17.6 Hz, 1H), 1.443 (s, 3H), 1.413 (s, 3H) 3 H) 1.292 (s, 3H), 1.287 (s, 3H);
MS(m/z) 399 (M+H)+.MS ( m / z ) 399 (M + H) + .
실시예Example 36. 3,4,5- 36. 3,4,5- 트리아세톡시Triacetoxy -- 벤조인산Benzoic acid 2,2-디메틸-8-옥소-3,4- 2,2-dimethyl-8-oxo-3,4- 디하이드로Dehydro -- 2H,8H2H, 8H -- 피라노[3,2-g]크로멘Pyrano [3,2-g] chromen -3-일-에스터(34c)의 제조Preparation of 3-yl-ester 34c
단계 1.Step 1.
상기 실시예 34의 반응식에서 나타난 바와 같이 1구 라운드 플라스크에 10당량의 아세트산 무수물을 넣고 1당량의 3,4,5-트리히드록시 벤조인산과 10당량의 피리딘을 첨가하였다. 이를 자석교반기에서 하룻동안 교반한 뒤, 감압농축 하였다. 농축액은 이동상(n-헥산 : 에틸아세테이드 = 5:1 ~ 1:1)을 사용하여 실리카겔 컬럼 크로마토그래피 법으로 분리하였으며, 순수한 생성물을 얻었다. As shown in the reaction scheme of Example 34, 10 equivalents of acetic anhydride was added to a 1-neck round flask, and 1 equivalent of 3,4,5-trihydroxy benzoic acid and 10 equivalents of pyridine were added thereto. After stirring for one day in a magnetic stirrer, it was concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 5: 1 ~ 1: 1) to obtain a pure product.
단계 2 및 단계 3Step 2 and Step 3
상기 실시예 34의 제 2단계에서 1구 라운드 플라스크에 1.5당량의 벤조인산대신 3,4,5-트리아세톡시 벤조인산으로 바꾸는 점만 제외하고 실시예 34의 제 2, 3단계와 동일한 공정을 수행하여, 하기 물성치를 갖는 3,4,5-트리아세톡시-벤조인산 2,2-디메틸-8-옥소-3,4-디하이드로-2H,8H-피라노[3,2-g]크로멘-3-일-에스터(34c)를 얻었다.The same process as in the second and third steps of Example 34 was carried out except that the first round flask was changed to 3,4,5-triacetoxy benzoic acid instead of 1.5 equivalents of benzoic acid in the second step of Example 34. 3,4,5-triacetoxy-benzoic acid 2,2-dimethyl-8-oxo-3,4-dihydro- 2H, 8H -pyrano [3,2-g] chromen having the following physical properties 3-yl-ester (34c) was obtained.
수율 : 28.8%;Yield: 28.8%;
고체상(Solid);Solid phase;
m.p 97℃;m.p 97 ° C .;
Rf= 0.44(n-헥산:에틸아세테이트=1:2);R f = 0.44 (n-hexane: ethyl acetate = 1: 2);
1H NMR(acetone-d6, 400MHz) :δ 7.848(d, J=9.6Hz, 1H), 7.740(s, 2H), 7.435(s, 1H), 6.765(s, 1H), 6.209(d, J=9.6Hz, 1H), 5.359(t, J=4.4, 17.6Hz, 1H), 3.403(dd, J=4.2, 17.6Hz, 1H), 3.123(dd, J=4.4, 17.6Hz, 1H), 2.317(s, 3H), 2.283(m, 6H), 1.479(s, 3H), 1.457(s, 3H); 1 H NMR (acetone-d 6 , 400 MHz): δ 7.848 (d, J = 9.6 Hz, 1H), 7.740 (s, 2H), 7.435 (s, 1H), 6.765 (s, 1H), 6.209 (d, J = 9.6 Hz, 1H), 5.359 (t, J = 4.4, 17.6 Hz, 1H), 3.403 (dd, J = 4.2, 17.6 Hz, 1H), 3.123 (dd, J = 4.4, 17.6 Hz, 1H), 2.317 (s, 3H), 2.283 (m, 6H), 1.479 (s, 3H), 1.457 (s, 3H);
MS(m/z) 525 (M+H)+.MS ( m / z ) 525 (M + H) + .
실험예 1. 세포독성 측정Experimental Example 1. Measurement of cytotoxicity
시험관내 세포독성 측정에는 A549 폐암세포, HCT15 대장암세포 및 ACHN 직장암세포를 사용하였는데 이들의 배양액은 모두 L-글루타민(glutamine)이 포함된 RPMI 1640 배지에 56℃ 수조에서 30분간 가온하여 불활성화시킨 우태혈청(FBS)을 10% 포함하고 1% 항생제(penicillin-G 10만units/streptomycin 100 ㎎)와 탄산수소나트륨(NaHCO3) 2 g을 첨가하여 제조하였다. A549 lung cancer cells, HCT15 colon cancer cells, and ACHN rectal cancer cells were used for in vitro cytotoxicity measurement, and all of their cultures were incubated in a RPMI 1640 medium containing L-glutamine (glutamine) for 30 minutes in a 56 ° C water bath and inactivated. It was prepared by adding 10% serum (FBS) and adding 1% antibiotic (penicillin-G 100,000 units / streptomycin 100 mg) and 2 g of sodium bicarbonate (NaHCO 3 ).
10% FBS가 첨가된 RPMI 1640으로 5% CO2, 37℃의 조건에서 세포들을 배양하며 사용하였다. 각각의 암세포를 2×104 cells을 일정농도의 시료와 섞어 웰 당 100 ㎕씩 96 웰 플레이트에 분주하였다. 이를 48시간 배양한 후 배양액을 모두 버리고 B16-BL6, A549 세포에 MTT(5 ㎎/㎖) 10 ㎕씩 넣고 4시간 동안 배양하였다. 배양이 끝난 플레이트를 PBS로 세척한 후 DMSO 100 ㎕를 넣고 상온에서 20분 방치한 후 ELISA reader로 570 nm에서 흡광도를 측정하였다. RPMI 1640 to which 10% FBS was added was used while culturing the cells at 5% CO 2 , 37 ° C. Each cancer cell was mixed with 2 × 10 4 cells with a constant concentration of sample and dispensed into a 96 well plate at 100 μl per well. After 48 hours of incubation, the culture medium was discarded and 10 μl of MTT (5 mg / ml) was added to B16-BL6 and A549 cells, followed by 4 hours of incubation. After the culture plate was washed with PBS, 100 μl of DMSO was added thereto, and the plate was left at room temperature for 20 minutes, and the absorbance was measured at 570 nm with an ELISA reader.
실험예 2. 데쿠르신 유도체의 항암활성 평가Experimental Example 2. Evaluation of anticancer activity of decursin derivatives
참당귀에서 분리한 데쿠르신은 ATCC(American Type Culture Collection)에서 구입한 인간 유래 암세포(human erythroleukemic), K562(ED50 48uM), HL-60(ED50 42uM) 및 폐암세포인 A549(ED50 39uM)에 대해서 강한 항암효과를 나타냈다(Ahn KS et al., Decursin: A cytotoxic agent and protein kinase C activator from the root of angelica gigas, Planta Med. 62, pp.7-9, 1996). 또한 데쿠르신은 ATCC(American Type Culture Collection)에서 구입한 인간 유래 암세포(human erythroleukemic)인 K562에 대해서 50uM의 농도에서 54%의 생존 억제효과를 나타내었다 (Kim, H. H. et al., Involvement of PKC and ROS in the cytotoxic mechanism of anti-leukemic decursin and its derivatives and their structure-activity relationship in human K562 erythroleukemia and U937 myeloleukemia cells. Cancer Lett. 223, pp. 191, 2005).Decursins isolated from Angelica gigas were human erythroleukemic (KCC), K562 (ED 50 48uM), HL-60 (ED 50 42uM), and lung cancer cells A549 (ED 50 39uM) purchased from American Type Culture Collection (ATCC). (Ahn KS et al., Decursin: A cytotoxic agent and protein kinase C activator from the root of angelica gigas, Planta Med. 62 , pp . 7-9, 1996). In addition, decursin showed 54% survival inhibition against human erythroleukemic K562 purchased from ATCC (American Type Culture Collection) at a concentration of 50 uM (Kim, HH et al., Involvement of PKC and ROS in the cytotoxic mechanism of anti- leukemic decursin and its derivatives and their structure-activity relationship in human K562 erythroleukemia and U937 myeloleukemia cells. Cancer Lett . 223 , pp. 191, 2005).
본 연구에서 합성한 여러 가지 데쿠르신 유도체들의 폐암세포 (A549), 결장암세포(HCT15), 직장암세포(ACHN) (ATCC(American Type Culture Collection)에서 구입) 총 3종의 암세포에 대한 항암효과를 하기 표 4에 나타내었다. 실험 결과, 10uM 데쿠르신(1b) 및 알킬기 구조를 갖는 유도체들(2b-12b)로 48시간 처리한 시험군들은 세가지 암세포에 대해서 전혀 세포독성 효과를 나타내지 않았다. 이에 비해서 시나모일 구조를 지닌 유도체(13c-18c) 처리군들은 강한 세포독성 효과를 나타내었다. 특히 화합물(14c) 물질의 경우에 A549, HCT15 및 ACHN 암세포에 대한 생존율이 각각 33%, 12% 및 43%로써 가장 강한 세포독성 효과를 나타내었다. 또한 벤조일 구조를 지닌 유도체들(26c-29c)은 약한 세포독성 효과를 나타내었다. 결과적으로 항암작용을 나타내기 위한 데쿠르신 유도체의 구조는 알킬기보다는 시나모일기 및 벤조일기와 같은 방향족 작용기를 지닌 구조임을 확인할 수 있었다 (표 10 참조). The anticancer effects of three types of decancin derivatives synthesized in this study were lung cancer cells (A549), colon cancer cells (HCT15) and rectal cancer cells (ACHN) (purchased from the American Type Culture Collection). Table 4 shows. As a result, the test groups treated with 10 uM decursin (1b) and derivatives having alkyl group structure (2b-12b) for 48 hours showed no cytotoxic effect on all three cancer cells. In contrast, the cinnamoyl derivative (13c-18c) treatment group showed a strong cytotoxic effect. In particular, the compound (14c) material showed the strongest cytotoxic effect on the A549, HCT15 and ACHN cancer cells 33%, 12% and 43% respectively. In addition, the benzoyl derivatives (26c-29c) showed a weak cytotoxic effect. As a result, the structure of the decursin derivative for showing anticancer activity was confirmed to have a structure having aromatic functional groups such as cinnamoyl group and benzoyl group rather than alkyl group (see Table 10).
하기에 상기 조성물의 제제예를 설명하나, 이는 본 발명을 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다. Examples of the formulation of the composition are described below, but are not intended to limit the present invention but to explain in detail only.
제제예 1. 산제의 제조Formulation Example 1 Preparation of Powder
데쿠르시놀 유도체 (14C) 20 mgDecursinol derivative (14C) 20 mg
유당 100 mgLactose 100 mg
탈크 10 mgTalc 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다. The above ingredients are mixed and filled in an airtight cloth to prepare a powder.
제제예 2. 정제의 제조Formulation Example 2 Preparation of Tablet
데쿠르시놀 유도체 (14C) 10 mgDecursinol derivative (14C) 10 mg
옥수수전분 100 mgCorn starch 100 mg
유당 100 mgLactose 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다. After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.
제제예 3. 캅셀제의 제조Formulation Example 3 Preparation of Capsule
데쿠르시놀 유도체 (14C) 10 mgDecursinol derivative (14C) 10 mg
결정성 셀룰로오스 3 mg3 mg of crystalline cellulose
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mgMagnesium Stearate 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다. According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
제제예 4. 주사제의 제조Formulation Example 4 Preparation of Injection
데쿠르시놀 유도체 (14C) 10 mgDecursinol derivative (14C) 10 mg
만니톨 180 mgMannitol 180 mg
주사용 멸균 증류수 2974 mgSterile distilled water for injection 2974 mg
Na2HPO412H2O 26 mgNa 2 HPO 4 12H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조한다. According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).
제제예 5. 액제의 제조Formulation Example 5 Preparation of Liquid
데쿠르시놀 유도체 (14C) 20 mgDecursinol derivative (14C) 20 mg
이성화당 10 g10 g of isomerized sugar
만니톨 5 g5 g of mannitol
정제수 적량Purified water
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다. According to the conventional method of preparing a liquid solution, each component is added to the purified water to dissolve it, the lemon flavor is added appropriately, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by the addition of purified water, and then filled in a brown bottle. The solution is prepared by sterilization.
제제예 6. 건강 식품의 제조Formulation Example 6 Preparation of Healthy Food
데쿠르시놀 유도체 (14C) 1000 ㎎Decursinol derivative (14C) 1000 mg
비타민 혼합물 적량Vitamin mixture proper amount
비타민 A 아세테이트 70 ㎍70 μg of Vitamin A Acetate
비타민 E 1.0 ㎎Vitamin E 1.0 mg
비타민 B1 0.13 ㎎Vitamin B1 0.13 mg
비타민 B2 0.15 ㎎Vitamin B2 0.15 mg
비타민 B6 0.5 ㎎Vitamin B6 0.5 mg
비타민 B12 0.2 ㎍0.2 μg of vitamin B12
비타민 C 10 ㎎Vitamin C 10 mg
비오틴 10 ㎍10 μg biotin
니코틴산아미드 1.7 ㎎Nicotinic Acid 1.7 mg
엽산 50 ㎍Folate 50 ㎍
판토텐산 칼슘 0.5 ㎎Calcium Pantothenate 0.5mg
무기질 혼합물 적량Mineral mixture
황산제1철 1.75 ㎎Ferrous Sulfate 1.75 mg
산화아연 0.82 ㎎Zinc Oxide 0.82 mg
탄산마그네슘 25.3 ㎎Magnesium carbonate 25.3 mg
제1인산칼륨 15 ㎎Potassium monophosphate 15 mg
제2인산칼슘 55 ㎎Dibasic calcium phosphate 55 mg
구연산칼륨 90 ㎎Potassium Citrate 90 mg
탄산칼슘 100 ㎎Calcium Carbonate 100 mg
염화마그네슘 24.8 ㎎Magnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다. Although the composition ratio of the above-mentioned vitamin and mineral mixtures is mixed with a component suitable for a health food in a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method. The granules may be prepared and used for preparing a health food composition according to a conventional method.
제제예 7. 건강 음료의 제조Formulation Example 7 Preparation of Healthy Drink
데쿠르시놀 유도체 (14C) 1000 ㎎Decursinol derivative (14C) 1000 mg
구연산 1000 ㎎Citric acid 1000 mg
올리고당 100 g100 g oligosaccharides
매실농축액 2 gPlum concentrate 2 g
타우린 1 g1 g of taurine
정제수를 가하여 전체 900 ㎖Add 900 ml of purified water
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2ℓ용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다. After mixing the above components according to a conventional healthy beverage manufacturing method, and then stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 L container, sealed and sterilized and then refrigerated and stored in the present invention For the preparation of healthy beverage compositions.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 수요계층, 수요국가, 사용 용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is a composition suitable for a preferred beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, use purpose.
상술한 바와 같이, 본 발명의 데쿠르신 유도체(decursin derivative) 화합물들은 폐암세포인 A549, 대장암세포인 HCT15 및 직장암세포인 ACHN와 같은 암세포에 대한 세포독성효과를 확인하여 암 질환의 예방 및 치료를 위한 약학 조성물 및 건강기능식품을 제공할 수 있다.As described above, the decursin derivative compounds of the present invention confirm the cytotoxic effects on cancer cells such as lung cancer cells A549, colon cancer cells HCT15 and rectal cancer cells ACHN for the prevention and treatment of cancer diseases. Pharmaceutical compositions and nutraceuticals can be provided.
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KR20200087591A (en) | 2019-01-11 | 2020-07-21 | 충남대학교산학협력단 | A pharmaceutical composition comprising decursin derivatives for preventing or treating CYP4 family related diseases |
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KR101204483B1 (en) | 2010-04-13 | 2012-11-26 | 한림대학교 산학협력단 | Decursinol derivatives, method of the same and pharmaceutical composition comprising same |
WO2011129516A1 (en) * | 2010-04-13 | 2011-10-20 | 한림대학교 산학협력단 | Decursinol derivative, a production method for the same and a pharmaceutical composition comprising the same |
KR101585450B1 (en) * | 2011-01-27 | 2016-01-19 | 대우제약 주식회사 | Analgesic and antipyretic compositions containing Decursinol derivatives |
US9249153B2 (en) | 2011-03-18 | 2016-02-02 | Pusan National University Industry-University Cooperation Foundation | Pharmaceutical composition for treating aging-associated diseases, containing progerin expression inhibitor as active ingredient, and screening method of said progerin expression inhibitor |
KR101407044B1 (en) * | 2012-03-16 | 2014-07-04 | 충남대학교산학협력단 | Pharmaceutical Composition for Preventing or Treating Aging-related Diseases Comprising Blocker of Progerin and Lamin A Binding and Screening Method Thereof |
ES2753650T3 (en) * | 2014-06-30 | 2020-04-13 | Nat Univ Pusan Ind Univ Coop Found | New compound to inhibit the binding between DX2 protein and p14 / ARF protein, and pharmaceutical composition to treat or prevent cancer disease that contains the same as an effective ingredient |
CN112480141A (en) * | 2020-12-10 | 2021-03-12 | 吉林大学珠海学院 | Pyranocoumarin derivative and preparation method and application thereof |
KR20240127661A (en) * | 2023-02-16 | 2024-08-23 | (주)재인알앤피 | Novel decursin derivatives and use thereof for preventing or treating non-small cell lung cancer |
Citations (1)
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KR0176413B1 (en) | 1993-09-07 | 1999-03-20 | 서정욱 | Decursin as an anti-tumour agent |
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JP2006094140A (en) * | 2004-09-24 | 2006-04-06 | Murata Mfg Co Ltd | Piezoelectric resonator and its manufacturing method, piezoelectric filter, and duplexer |
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2007
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- 2007-07-04 WO PCT/KR2007/003257 patent/WO2008004817A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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KR0176413B1 (en) | 1993-09-07 | 1999-03-20 | 서정욱 | Decursin as an anti-tumour agent |
Non-Patent Citations (1)
Title |
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CANCER LETTERS. (2005), Vol.223, No.2, pages 191-201 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101674145B1 (en) | 2015-08-12 | 2016-11-08 | 충남대학교산학협력단 | Decursinol-carbamate derivatives, and pharmaceutical composition containing the same for preventing or treating cancer |
KR20200087591A (en) | 2019-01-11 | 2020-07-21 | 충남대학교산학협력단 | A pharmaceutical composition comprising decursin derivatives for preventing or treating CYP4 family related diseases |
Also Published As
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WO2008004817A1 (en) | 2008-01-10 |
KR20080004332A (en) | 2008-01-09 |
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